Compositions and methods relating to lung specific genes and proteins

ABSTRACT

The present invention relates to newly identified nucleic acids and polypeptides present in normal and neoplastic lung cells, including fragments, variants and derivatives of the nucleic acids and polypeptides. The present invention also relates to antibodies to the polypeptides of the invention, as well as agonists and antagonists of the polypeptides of the invention. The invention also relates to compositions comprising the nucleic acids, polypeptides, antibodies, variants, derivatives, agonists and antagonists of the invention and methods for the use of these compositions. These uses include identifying, diagnosing, monitoring, staging, imaging and treating lung cancer and non-cancerous disease states in lung, identifying lung tissue, monitoring and identifying and/or designing agonists and antagonists of polypeptides of the invention. The uses also include gene therapy, production of transgenic animals and cells, and production of engineered lung tissue for treatment and research.

[0001] This application claims the benefit of priority from U.S. Provisional Application Serial No. 60/252,500 filed Nov. 22, 2000, which is herein incorporated by reference in its entirety.

FIELD OF THE INVENTION

[0002] The present invention relates to newly identified nucleic acid molecules and polypeptides present in normal and neoplastic lung cells, including fragments, variants and derivatives of the nucleic acids and polypeptides. The present invention also relates to antibodies to the polypeptides of the invention, as well as agonists and antagonists of the polypeptides of the invention. The invention also relates to compositions comprising the nucleic acids, polypeptides, antibodies, variants, derivatives, agonists and antagonists of the invention and methods for the use of these compositions. These uses include identifying, diagnosing, monitoring, staging, imaging and treating lung cancer and non-cancerous disease states in lung, identifying lung tissue and monitoring and identifying and/or designing agonists and antagonists of polypeptides of the invention. The uses also include gene therapy, production of transgenic animals and cells, and production of engineered lung tissue for treatment and research.

BACKGROUND OF THE INVENTION

[0003] Throughout the last hundred years, the incidence of lung cancer has steadily increased, so much so that now in many countries, it is the most common cancer. In fact, lung cancer is the second most prevalent type of cancer for both men and women in the United States and is the most common cause of cancer death in both sexes. Lung cancer deaths have increased ten-fold in both men and women since 1930, primarily due to an increase in cigarette smoking, but also due to an increased exposure to arsenic, asbestos, chromates, chloromethyl ethers, nickel, polycyclic aromatic hydrocarbons and other agents. See Scott, Lung Cancer: A Guide to Diagnosis and Treatment, Addicus Books (2000) and Alberg et al., in Kane et al. (eds.) Biology of Lung Cancer, pp.11-52, Marcel Dekker, Inc. (1998). Lung cancer may result from a primary tumor originating in the lung or a secondary tumor which has spread from another organ such as the bowel or breast. Although there are over a dozen types of lung cancer, over 90% fall into two categories: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). See Scott, supra. About 20-25% of all lung cancers are characterized as SCLC, while 70-80% are diagnosed as NSCLC. Id. A rare type of lung cancer is mesothelioma, which is generally caused by exposure to asbestos, and which affects the pleura of the lung. Lung cancer is usually diagnosed or screened for by chest x-ray, CAT scans, PET scans, or by sputum cytology. A diagnosis of lung cancer is usually confirmed by biopsy of the tissue. Id.

[0004] SCLC tumors are highly metastatic and grow quickly. By the time a patient has been diagnosed with SCLC, the cancer has usually already spread to other parts of the body, including lymph nodes, adrenals, liver, bone, brain and bone marrow. See Scott, supra; Van Houtte et al. (eds.), Progress and Perspective in the Treatment of Lung Cancer, Springer-Verlag (1999). Because the disease has usually spread to such an extent that surgery is not an option, the current treatment of choice is chemotherapy plus chest irradiation. See Van Houtte, supra. The stage of disease is a principal predictor of long-term survival. Less than 5% of patients with extensive disease that has spread beyond one lung and surrounding lymph nodes, live longer than two years. Id. However, the probability of five-year survival is three to four times higher if the disease is diagnosed and treated when it is still in a limited stage, i.e., not having spread beyond one lung. Id.

[0005] NSCLC is generally divided into three types: squamous cell carcinoma, adenocarcinoma and large cell carcinoma. Both squamous cell cancer and adenocarcinoma develop from the cells that line the airways; however, adenocarcinoma develops from the goblet cells that produce mucus. Large cell lung cancer has been thus named because the cells look large and rounded when viewed microscopically, and generally are considered relatively undifferentiated. See Yesner, Atlas of Lung Cancer, Lippincott-Raven (1998).

[0006] Secondary lung cancer is a cancer initiated elsewhere in the body that has spread to the lungs. Cancers that metastasize to the lung include, but are not limited to, breast cancer, melanoma, colon cancer and Hodgkin's lymphoma. Treatment for secondary lung cancer may depend upon the source of the original cancer. In other words, a lung cancer that originated from breast cancer may be more responsive to breast cancer treatments and a lung cancer that originated from the colon cancer may be more responsive to colon cancer treatments.

[0007] The stage of a cancer indicates how far it has spread and is an important indicator of the prognosis. In addition, staging is important because treatment is often decided according to the stage of a cancer. SCLC is divided into two stages: limited disease, i.e., cancer that can only be seen in one lung and in nearby lymph nodes; and extensive disease, i.e., cancer that has spread outside the lung to the chest or to other parts of the body. For most patients with SCLC, the disease has already progressed to lymph nodes or elsewhere in the body at the time of diagnosis. See Scott, supra. Even if spreading is not apparent on the scans, it is likely that some cancer cells may have spread away and traveled through the bloodstream or lymph system. In general, chemotherapy with or without radiotherapy is often the preferred treatment. The initial scans and tests done at first will be used later to see how well a patient is responding to treatment.

[0008] In contrast, non-small cell cancer may be divided into four stages. Stage I is highly localized cancer with no cancer in the lymph nodes. Stage II cancer has spread to the lymph nodes at the top of the affected lung. Stage III cancer has spread near to where the cancer started. This can be to the chest wall, the covering of the lung (pleura), the middle of the chest (mediastinum) or other lymph nodes. Stage IV cancer has spread to another part of the body. Stage I-III cancer is usually treated with surgery, with or without chemotherapy. Stage IV cancer is usually treated with chemotherapy and/or palliative care.

[0009] A number of chromosomal and genetic abnormalities have been observed in lung cancer. In NSCLC, chromosomal aberrations have been described on 3p, 9p, 11p, 15p and 17p, and chromosomal deletions have been seen on chromosomes 7, 11, 13 and 19. See Skarin (ed.), Multimodality Treatment of Lung Cancer, Marcel Dekker, Inc. (2000); Gemmill et al, pp. 465-502, in Kane, supra; Bailey-Wilson et al., pp. 53-98, in Kane, supra. Chromosomal abnormalities have been described on 1p, 3p, 5q, 6q, 8q, 13q and 17p in SCLC. Id. The loss of the short arm of chromosome 3p has also been seen in greater than 90% of SCLC tumors and approximately 50% of NSCLC tumors. Id.

[0010] A number of oncogenes and tumor suppressor genes have been implicated in lung cancer. See Mabry, pp. 391-412, in Kane, supra and Sclafani et al., pp. 295-316, in Kane, supra. In both SCLC and NSCLC, the p53 tumor suppressor gene is mutated in over 50% of lung cancers. See Yesner, supra. Another tumor suppressor gene, FHIT, which is found on chromosome 3p, is mutated by tobacco smoke. Id.; Skarin, supra. In addition, more than 95% of SCLCs and approximately 20-60% of NSCLCs have an absent or abnormal retinoblastoma (Rb) protein, another tumor suppressor gene. The ras oncogene (particularly K-ras) is mutated in 20-30% of NSCLC specimens and the c-erbB2 oncogene is expressed in 18% of stage 2 NSCLC and 60% of stage 4 NSCLC specimens. See Van Houtte, supra. Other tumor suppressor genes that are found in a region of chromosome 9, specifically in the region of 9p21, are deleted in many cancer cells, including p16^(INK4A) and p15^(INK4B). See Bailey-Wilson, supra; Sclafani et al., supra. These tumor suppressor genes may also be implicated in lung cancer pathogenesis.

[0011] In addition, many lung cancer cells produce growth factors that may act in an autocrine fashion on lung cancer cells. See Siegfried etaL., pp.317-336, in Kane, supra; Moody, pp. 337-370, in Kane, supra and Heasley et aL., 371-390, in Kane, supra. In SCLC, many tumor cells produce gastrin-releasing peptide (GRP), which is a proliferative growth factor for these cells. See Skarin, supra. Many NSCLC tumors express epidermal growth factor (EGF) receptors, allowing NSCLC cells to proliferate in response to EGF. Insulin-like growth factor (IGF-I) is elevated in greater than 95% of SCLC and greater than 80% of NSCLC tumors; it is thought to function as an autocrine growth factor. Id. Finally, stem cell factor (SCF, also known as steel factor or kit ligand) and c-Kit (a proto-oncoprotein tyrosine kinase receptor for SCF) are both expressed at high levels in SCLC, and thus may form an autocrine loop that increases proliferation. Id.

[0012] Although the majority of lung cancer cases are attributable to cigarette smoking, most smokers do not develop lung cancer. Epidemiological evidence has suggested that susceptibility to lung cancer may be inherited in a Mendelian fashion, and thus have an inherited genetic component. Bailey-Wilson, supra. Thus, it is thought that certain allelic variants at some genetic loci may affect susceptibility to lung cancer. Id. One way to identify which allelic variants are likely to be involved in lung cancer susceptibility, as well as susceptibility to other diseases, is to look at allelic variants of genes that are highly expressed in lung.

[0013] The lung is susceptible to a number of other debilitating diseases as well, including, without limitation, emphysema, pneumonia, cystic fibrosis and asthma. See Stockley (ed.), Molecular Biology of the Lung, Volume I: Emphysema and Infection, Birkhauser Verlag (1999), hereafter Stockley I, and Stockley (ed.), Molecular Biology of the Lung, Volume II: Asthma and Cancer, Birkhauser Verlag (1999), hereafter Stockley II. The cause of many these disorders is still not well understood and there are few, if any, good treatment options for many of these noncancerous lung disorders. Thus, there also remains a need for understanding of various noncancerous lung disorders and for identify treatments for these diseases.

[0014] The development and differentiation of the lung tissue during embryonic development is also very important. All of the epithelial cells of the respiratory tract, including those of the lung and bronchi, are derived from the primitive endodermal cells that line the embryonic outpouching. See Yesner, supra. During embryonic development, multipotent endodermal stem cells differentiate into many different types of specialized cells, which include ciliated cells for moving inhaled particles, goblet cells for producing mucus, Kulchitsky's cells for endocrine function, and Clara cells and type II pneumocytes for secreting surfactant protein. Id. Improper development and differentiation may cause respiratory disorders and distress in infants, particularly in premature infants, whose lungs cannot produce sufficient surfactant when they are born. Further, some lung cancer cells, particularly small cell carcinomas, appear multipotent, and can spontaneously differentiate into a number of cell types, including small cell carcinoma, adenocarcinoma and squamous cell carcinoma. Id. Thus, a better understanding of lung development and differentiation may help facilitate understanding of lung cancer initiation and progression.

[0015] Accordingly, there is a great need for more sensitive and accurate methods for predicting whether a person is likely to develop lung cancer, for diagnosing lung cancer, for monitoring the progression of the disease, for staging the lung cancer, for determining whether the lung cancer has metastasized and for imaging the lung cancer. There is also a need for better treatment of lung cancer. There is also a great need for diagnosing and treating noncancerous lung disorders such as emphysema, pneumonia, lung infection, pulmonary fibrosis, cystic fibrosis and asthma. There is also a need for compositions and methods of using compositions that are capable of identifying lung tissue for forensic purposes and for determining whether a particular cell or tissue exhibits lung-specific characteristics.

SUMMARY OF THE INVENTION

[0016] The present invention solves these and other needs in the art by providing nucleic acid molecules and polypeptides as well as antibodies, agonists and antagonists, thereto that may be used to identify, diagnose, monitor, stage, image and treat lung cancer and non-cancerous disease states in lung; identify and monitor lung tissue; and identify and design agonists and antagonists of polypeptides of the invention. The invention also provides gene therapy, methods for producing transgenic animals and cells, and methods for producing engineered lung tissue for treatment and research.

[0017] Accordingly, one object of the invention is to provide nucleic acid molecules that are specific to lung cells, lung tissue and/or the lung organ. These lung specific nucleic acids (LSNAs) may be a naturally-occurring cDNA, genomic DNA, RNA, or a fragment of one of these nucleic acids, or may be a non-naturally-occurring nucleic acid molecule. If the LSNA is genomic DNA, then the LSNA is a lung specific gene (LSG). In a preferred embodiment, the nucleic acid molecule encodes a polypeptide that is specific to lung. In a more preferred embodiment, the nucleic acid molecule encodes a polypeptide that comprises an amino acid sequence of SEQ ID NO: 165 through 284. In another highly preferred embodiment, the nucleic acid molecule comprises a nucleic acid sequence of SEQ ID NO: 1 through 164. By nucleic acid molecule, it is also meant to be inclusive of sequences that selectively hybridize or exhibit substantial sequence similarity to a nucleic acid molecule encoding an LSP, or that selectively hybridize or exhibit substantial sequence similarity to an LSNA, as well as allelic variants of a nucleic acid molecule encoding an LSP, and allelic variants of an LSNA. Nucleic acid molecules comprising a part of a nucleic acid sequence that encodes an LSP or that comprises a part of a nucleic acid sequence of an LSNA are also provided.

[0018] A related object of the present invention is to provide a nucleic acid molecule comprising one or more expression control sequences controlling the transcription and/or translation of all or a part of an LSNA. In a preferred embodiment, the nucleic acid molecule comprises one or more expression control sequences controlling the transcription and/or translation of a nucleic acid molecule that encodes all or a fragment of an LSP.

[0019] Another object of the invention is to provide vectors and/or host cells comprising a nucleic acid molecule of the instant invention. In a preferred embodiment, the nucleic acid molecule encodes all or a fragment of an LSP. In another preferred embodiment, the nucleic acid molecule comprises all or a part of an LSNA.

[0020] Another object of the invention is to provided methods for using the vectors and host cells comprising a nucleic acid molecule of the instant invention to recombinantly produce polypeptides of the invention.

[0021] Another object of the invention is to provide a polypeptide encoded by a nucleic acid molecule of the invention. In a preferred embodiment, the polypeptide is an LSP. The polypeptide may comprise either a fragment or a full-length protein as well as a mutant protein (mutein), fusion protein, homologous protein or a polypeptide encoded by an allelic variant of an LSP.

[0022] Another object of the invention is to provide an antibody that specifically binds to a polypeptide of the instant invention.

[0023] Another object of the invention is to provide agonists and antagonists of the nucleic acid molecules and polypeptides of the instant invention.

[0024] Another object of the invention is to provide methods for using the nucleic acid molecules to detect or amplify nucleic acid molecules that have similar or identical nucleic acid sequences compared to the nucleic acid molecules described herein. In a preferred embodiment, the invention provides methods of using the nucleic acid molecules of the invention for identifying, diagnosing, monitoring, staging, imaging and treating lung cancer and non-cancerous disease states in lung. In another preferred embodiment, the invention provides methods of using the nucleic acid molecules of the invention for identifying and/or monitoring lung tissue. The nucleic acid molecules of the instant invention may also be used in gene therapy, for producing transgenic animals and cells, and for producing engineered lung tissue for treatment and research.

[0025] The polypeptides and/or antibodies of the instant invention may also be used to identify, diagnose, monitor, stage, image and treat lung cancer and non-cancerous disease states in lung. The invention provides methods of using the polypeptides of the invention to identify and/or monitor lung tissue, and to produce engineered lung tissue.

[0026] The agonists and antagonists of the instant invention may be used to treat lung cancer and non-cancerous disease states in lung and to produce engineered lung tissue.

[0027] Yet another object of the invention is to provide a computer readable means of storing the nucleic acid and amino acid sequences of the invention. The records of the computer readable means can be accessed for reading and displaying of sequences for comparison, alignment and ordering of the sequences of the invention to other sequences.

DETAILED DESCRIPTION OF THE INVENTION

[0028] Definitions and General Techniques

[0029] Unless otherwise defined herein, scientific and technical terms used in connection with the present invention shall have the meanings that are commonly understood by those of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. Generally, nomenclatures used in connection with, and techniques of, cell and tissue culture, molecular biology, immunology, microbiology, genetics and protein and nucleic acid chemistry and hybridization described herein are those well-known and commonly used in the art. The methods and techniques of the present invention are generally performed according to conventional methods well-known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification unless otherwise indicated. See, e.g., Sambrook et al., Molecular Cloning: A Laboratory Manual, 2d ed., Cold Spring Harbor Laboratory Press (1989) and Sambrook et al., Molecular Cloning: A Laboratory Manual, 3d ed., Cold Spring Harbor Press (2001); Ausubel et al., Current Protocols in Molecular Biology, Greene Publishing Associates (1992, and Supplements to 2000); Ausubel et al., Short Protocols in Molecular Biology: A Compendium of Methods from Current Protocols in Molecular Biology—4^(th) Ed., Wiley & Sons (1999); Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press (1990); and Harlow and Lane, Using Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press (1999); each of which is incorporated herein by reference in its entirety.

[0030] Enzymatic reactions and purification techniques are performed according to manufacturer's specifications, as commonly accomplished in the art or as described herein. The nomenclatures used in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those well-known and commonly used in the art. Standard techniques are used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients.

[0031] The following terms, unless otherwise indicated, shall be understood to have the following meanings:

[0032] A “nucleic acid molecule” of this invention refers to a polymeric form of nucleotides and includes both sense and antisense strands of RNA, cDNA, genomic DNA, and synthetic forms and mixed polymers of the above. A nucleotide refers to a ribonucleotide, deoxynucleotide or a modified form of either type of nucleotide. A “nucleic acid molecule” as used herein is synonymous with “nucleic acid” and “polynucleotide.” The term “nucleic acid molecule” usually refers to a molecule of at least 10 bases in length, unless otherwise specified. The term includes single- and double-stranded forms of DNA. In addition, a polynucleotide may include either or both naturally-occurring and modified nucleotides linked together by naturally-occurring and/or non-naturally occurring nucleotide linkages.

[0033] The nucleic acid molecules may be modified chemically or biochemically or may contain non-natural or derivatized nucleotide bases, as will be readily appreciated by those of skill in the art. Such modifications include, for example, labels, methylation, substitution of one or more of the naturally occurring nucleotides with an analog, intemucleotide modifications such as uncharged linkages (e.g., methyl phosphonates, phosphotriesters, phosphoramidates, carbamates, etc.), charged linkages (e.g., phosphorothioates, phosphorodithioates, etc.), pendent moieties (e.g., polypeptides), intercalators (e.g., acridine, psoralen, etc.), chelators, alkylators, and modified linkages (e.g., alpha anomeric nucleic acids, etc.) The term “nucleic acid molecule” also includes any topological conformation, including single-stranded, double-stranded, partially duplexed, triplexed, hairpinned, circular and padlocked conformations. Also included are synthetic molecules that mimic polynucleotides in their ability to bind to a designated sequence via hydrogen bonding and other chemical interactions. Such molecules are known in the art and include, for example, those in which peptide linkages substitute for phosphate linkages in the backbone of the molecule.

[0034] A “gene” is defined as a nucleic acid molecule that comprises a nucleic acid sequence that encodes a polypeptide and the expression control sequences that surround the nucleic acid sequence that encodes the polypeptide. For instance, a gene may comprise a promoter, one or more enhancers, a nucleic acid sequence that encodes a polypeptide, downstream regulatory sequences and, possibly, other nucleic acid sequences involved in regulation of the expression of an RNA. As is well-known in the art, eukaryotic genes usually contain both exons and introns. The term “exon” refers to a nucleic acid sequence found in genomic DNA that is bioinformatically predicted and/or experimentally confirmed to contribute a contiguous sequence to a mature mRNA transcript. The term “intron” refers to a nucleic acid sequence found in genomic DNA that is predicted and/or confirmed to not contribute to a mature mRNA transcript, but rather to be “spliced out” during processing of the transcript.

[0035] A nucleic acid molecule or polypeptide is “derived” from a particular species if the nucleic acid molecule or polypeptide has been isolated from the particular species, or if the nucleic acid molecule or polypeptide is homologous to a nucleic acid molecule or polypeptide isolated from a particular species.

[0036] An “isolated” or “substantially pure” nucleic acid or polynucleotide (e.g., an RNA, DNA or a mixed polymer) is one which is substantially separated from other cellular components that naturally accompany the native polynucleotide in its natural host cell, e.g., ribosomes, polymerases, or genomic sequences with which it is naturally associated. The term embraces a nucleic acid or polynucleotide that (1) has been removed from its naturally occurring environment, (2) is not associated with all or a portion of a polynucleotide in which the “isolated polynucleotide” is found in nature, (3) is operatively linked to a polynucleotide which it is not linked to in nature, (4) does not occur in nature as part of a larger sequence or (5) includes nucleotides or intemucleoside bonds that are not found in nature. The term “isolated” or “substantially pure” also can be used in reference to recombinant or cloned DNA isolates, chemically synthesized polynucleotide analogs, or polynucleotide analogs that are biologically synthesized by heterologous systems. The term “isolated nucleic acid molecule” includes nucleic acid molecules that are integrated into a host cell chromosome at a heterologous site, recombinant fusions of a native fragment to a heterologous sequence, recombinant vectors present as episomes or as integrated into a host cell chromosome.

[0037] A “part” of a nucleic acid molecule refers to a nucleic acid molecule that comprises a partial contiguous sequence of at least 10 bases of the reference nucleic acid molecule. Preferably, a part comprises at least 15 to 20 bases of a reference nucleic acid molecule. In theory, a nucleic acid sequence of 17 nucleotides is of sufficient length to occur at random less frequently than once in the three gigabase human genome, and thus to provide a nucleic acid probe that can uniquely identify the reference sequence in a nucleic acid mixture of genomic complexity. A preferred part is one that comprises a nucleic acid sequence that can encode at least 6 contiguous amino acid sequences (fragments of at least 18 nucleotides) because they are useful in directing the expression or synthesis of peptides that are useful in mapping the epitopes of the polypeptide encoded by the reference nucleic acid. See, e.g., Geysen et al., Proc. Natl. Acad. Sci. USA 81:3998-4002 (1984); and U.S. Pat. Nos. 4,708,871 and 5,595,915, the disclosures of which are incorporated herein by reference in their entireties. A part may also comprise at least 25, 30, 35 or 40 nucleotides of a reference nucleic acid molecule, or at least 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400 or 500 nucleotides of a reference nucleic acid molecule. A part of a nucleic acid molecule may comprise no other nucleic acid sequences. Alternatively, a part of a nucleic acid may comprise other nucleic acid sequences from other nucleic acid molecules.

[0038] The term “oligonucleotide” refers to a nucleic acid molecule generally comprising a length of 200 bases or fewer. The term often refers to single-stranded deoxyribonucleotides, but it can refer as well to single- or double-stranded ribonucleotides, RNA:DNA hybrids and double-stranded DNAs, among others. Preferably, oligonucleotides are 10 to 60 bases in length and most preferably 12, 13, 14, 15, 16, 17, 18, 19 or 20 bases in length. Other preferred oligonucleotides are 25, 30, 35, 40, 45, 50, 55 or 60 bases in length. Oligonucleotides may be single-stranded, e.g. for use as probes or primers, or may be double-stranded, e.g. for use in the construction of a mutant gene. Oligonucleotides of the invention can be either sense or antisense oligonucleotides. An oligonucleotide can be derivatized or modified as discussed above for nucleic acid molecules.

[0039] Oligonucleotides, such as single-stranded DNA probe oligonucleotides, often are synthesized by chemical methods, such as those implemented on automated oligonucleotide synthesizers. However, oligonucleotides can be made by a variety of other methods, including in vitro recombinant DNA-mediated techniques and by expression of DNAs in cells and organisms. Initially, chemically synthesized DNAs typically are obtained without a 5′ phosphate. The 5′ ends of such oligonucleotides are not substrates for phosphodiester bond formation by ligation reactions that employ DNA ligases typically used to form recombinant DNA molecules. Where ligation of such oligonucleotides is desired, a phosphate can be added by standard techniques, such as those that employ a kinase and ATP. The 3′ end of a chemically synthesized oligonucleotide generally has a free hydroxyl group and, in the presence of a ligase, such as T4 DNA ligase, readily will form a phosphodiester bond with a 5′ phosphate of another polynucleotide, such as another oligonucleotide. As is well-known, this reaction can be prevented selectively, where desired, by removing the 5′ phosphates of the other polynucleotide(s) prior to ligation.

[0040] The term “naturally-occurring nucleotide” referred to herein includes naturally-occurring deoxyribonucleotides and ribonucleotides. The term “modified nucleotides” referred to herein includes nucleotides with modified or substituted sugar groups and the like. The term “nucleotide linkages” referred to herein includes nucleotides linkages such as phosphorothioate, phosphorodithioate, phosphoroselenoate, phosphorodiselenoate, phosphoroanilothioate, phoshoraniladate, phosphoroamidate, and the like. See e.g., LaPlanche et al. Nucl. Acids Res. 14:9081-9093 (1986); Stein et al. Nucl. Acids Res. 16:3209-3221 (1988); Zon et al. Anti-Cancer Drug Design 6:539-568 (1991); Zon et al., in Eckstein (ed.) Oligonucleotides and Analogues: A Practical Approach, pp. 87-108, Oxford University Press (1991); U.S. Pat. No. 5,151,510; Uhlmann and Peyman Chemical Reviews 90:543 (1990), the disclosures of which are hereby incorporated by reference.

[0041] Unless specified otherwise, the left hand end of a polynucleotide sequence in sense orientation is the 5′ end and the right hand end of the sequence is the 3′ end. In addition, the left hand direction of a polynucleotide sequence in sense orientation is referred to as the 5′ direction, while the right hand direction of the polynucleotide sequence is referred to as the 3′ direction. Further, unless otherwise indicated, each nucleotide sequence is set forth herein as a sequence of deoxyribonucleotides. It is intended, however, that the given sequence be interpreted as would be appropriate to the polynucleotide composition: for example, if the isolated nucleic acid is composed of RNA, the given sequence intends ribonucleotides, with uridine substituted for thymidine.

[0042] The term “allelic variant” refers to one of two or more alternative naturally-occurring forms of a gene, wherein each gene possesses a unique nucleotide sequence. In a preferred embodiment, different alleles of a given gene have similar or identical biological properties.

[0043] The term “percent sequence identity” in the context of nucleic acid sequences refers to the residues in two sequences which are the same when aligned for maximum correspondence. The length of sequence identity comparison may be over a stretch of at least about nine nucleotides, usually at least about 20 nucleotides, more usually at least about 24 nucleotides, typically at least about 28 nucleotides, more typically at least about 32 nucleotides, and preferably at least about 36 or more nucleotides. There are a number of different algorithms known in the art which can be used to measure nucleotide sequence identity. For instance, polynucleotide sequences can be compared using FASTA, Gap or Bestfit, which are programs in Wisconsin Package Version 10.0, Genetics Computer Group (GCG), Madison, Wis. FASTA, which includes, e.g., the programs FASTA2 and FASTA3, provides alignments and percent sequence identity of the regions of the best overlap between the query and search sequences (Pearson, Methods Enzymol. 183: 63-98 (1990); Pearson, Methods Mol. Biol. 132: 185-219 (2000); Pearson, Methods Enzymol. 266: 227-258 (1996); Pearson, J. Mol. Biol. 276: 71-84 (1998); herein incorporated by reference). Unless otherwise specified, default parameters for a particular program or algorithm are used. For instance, percent sequence identity between nucleic acid sequences can be determined using FASTA with its default parameters (a word size of 6 and the NOPAM factor for the scoring matrix) or using Gap with its default parameters as provided in GCG Version 6.1, herein incorporated by reference.

[0044] A reference to a nucleic acid sequence encompasses its complement unless otherwise specified. Thus, a reference to a nucleic acid molecule having a particular sequence should be understood to encompass its complementary strand, with its complementary sequence. The complementary strand is also useful, e.g., for antisense therapy, hybridization probes and PCR primers.

[0045] In the molecular biology art, researchers use the terms “percent sequence identity”, “percent sequence similarity” and “percent sequence homology” interchangeably. In this application, these terms shall have the same meaning with respect to nucleic acid sequences only.

[0046] The term “substantial similarity” or “substantial sequence similarity,” when referring to a nucleic acid or fragment thereof, indicates that, when optimally aligned with appropriate nucleotide insertions or deletions with another nucleic acid (or its complementary strand), there is nucleotide sequence identity in at least about 50%, more preferably 60% of the nucleotide bases, usually at least about 70%, more usually at least about 80%, preferably at least about 90%, and more preferably at least about 95-98% of the nucleotide bases, as measured by any well-known algorithm of sequence identity, such as FASTA, BLAST or Gap, as discussed above.

[0047] Alternatively, substantial similarity exists when a nucleic acid or fragment thereof hybridizes to another nucleic acid, to a strand of another nucleic acid, or to the complementary strand thereof, under selective hybridization conditions. Typically, selective hybridization will occur when there is at least about 55% sequence identity, preferably at least about 65%, more preferably at least about 75%, and most preferably at least about 90% sequence identity, over a stretch of at least about 14 nucleotides, more preferably at least 17 nucleotides, even more preferably at least 20, 25, 30, 35, 40, 50, 60, 70, 80, 90 or 100 nucleotides.

[0048] Nucleic acid hybridization will be affected by such conditions as salt concentration, temperature, solvents, the base composition of the hybridizing species, length of the complementary regions, and the number of nucleotide base mismatches between the hybridizing nucleic acids, as will be readily appreciated by those skilled in the art. “Stringent hybridization conditions” and “stringent wash conditions” in the context of nucleic acid hybridization experiments depend upon a number of different physical parameters. The most important parameters include temperature of hybridization, base composition of the nucleic acids, salt concentration and length of the nucleic acid. One having ordinary skill in the art knows how to vary these parameters to achieve a particular stringency of hybridization. In general, “stringent hybridization” is performed at about 25° C. below the thermal melting point (T_(m)) for the specific DNA hybrid under a particular set of conditions. “Stringent washing” is performed at temperatures about 5° C. lower than the T_(m) for the specific DNA hybrid under a particular set of conditions. The T_(m) is the temperature at which 50% of the target sequence hybridizes to a perfectly matched probe. See Sambrook (1989), supra, p.9.51, hereby incorporated by reference.

[0049] The T_(m) for a particular DNA-DNA hybrid can be estimated by the formula:

T _(m)=81.5° C.+16.6 (logio[Na⁺])+0.41 (fraction G+C)−0.63 (% formamide)−(600/1)

[0050] where 1 is the length of the hybrid in base pairs.

[0051] The T_(m) for a particular RNA-RNA hybrid can be estimated by the formula:

T _(m)=79.8° C.+18.5 (logio[Na⁺])+0.58 (fraction G+C)+11.8 (fraction G+C)²−0.35 (% formamide)−(820/1).

[0052] The T_(m) for a particular RNA-DNA hybrid can be estimated by the formula:

T_(m)=79.8° C.+18.5(logio[Na⁺])+0.58 (fraction G+C)+11.8 (fraction G+C)²−0.50 (% formamide)−(820/1).

[0053] In general, the T_(m) decreases by 1-1.5° C. for each 1% of mismatch between two nucleic acid sequences. Thus, one having ordinary skill in the art can alter hybridization and/or washing conditions to obtain sequences that have higher or lower degrees of sequence identity to the target nucleic acid. For instance, to obtain hybridizing nucleic acids that contain up to 10% mismatch from the target nucleic acid sequence, 10-15° C. would be subtracted from the calculated T_(m) of a perfectly matched hybrid, and then the hybridization and washing temperatures adjusted accordingly. Probe sequences may also hybridize specifically to duplex DNA under certain conditions to form triplex or other higher order DNA complexes. The preparation of such probes and suitable hybridization conditions are well-known in the art.

[0054] An example of stringent hybridization conditions for hybridization of complementary nucleic acid sequences having more than 100 complementary residues on a filter in a Southern or Northern blot or for screening a library is 50% formamide/6× SSC at 42° C. for at least ten hours and preferably overnight (approximately 16 hours). Another example of stringent hybridization conditions is 6× SSC at 68° C. without formamide for at least ten hours and preferably overnight. An example of moderate stringency hybridization conditions is 6× SSC at 55° C. without formamide for at least ten hours and preferably overnight. An example of low stringency hybridization conditions for hybridization of complementary nucleic acid sequences having more than 100 complementary residues on a filter in a Southern or Northern blot or for screening a library is 6× SSC at 42° C. for at least ten hours. Hybridization conditions to identify nucleic acid sequences that are similar but not identical can be identified by experimentally changing the hybridization temperature from 68° C. to 42° C. while keeping the salt concentration constant (6× SSC), or keeping the hybridization temperature and salt concentration constant (e.g. 42° C. and 6× SSC) and varying the formamide concentration from 50% to 0%. Hybridization buffers may also include blocking agents to lower background. These agents are well-known in the art. See Sambrook et al. (1989), supra, pages 8.46 and 9.46-9.58, herein incorporated by reference. See also Ausubel (1992), supra, Ausubel (1999), supra, and Sambrook (2001), supra.

[0055] Wash conditions also can be altered to change stringency conditions. An example of stringent wash conditions is a 0.2× SSC wash at 65° C. for 15 minutes (see Sambrook (1989), supra, for SSC buffer). Often the high stringency wash is preceded by a low stringency wash to remove excess probe. An exemplary medium stringency wash for duplex DNA of more than 100 base pairs is lx SSC at 45° C. for 15 minutes. An exemplary low stringency wash for such a duplex is 4× SSC at 40° C. for 15 minutes. In general, signal-to-noise ratio of 2× or higher than that observed for an unrelated probe in the particular hybridization assay indicates detection of a specific hybridization.

[0056] As defined herein, nucleic acid molecules that do not hybridize to each other under stringent conditions are still substantially similar to one another if they encode polypeptides that are substantially identical to each other. This occurs, for example, when a nucleic acid molecule is created synthetically or recombinantly using high codon degeneracy as permitted by the redundancy of the genetic code.

[0057] Hybridization conditions for nucleic acid molecules that are shorter than 100 nucleotides in length (e.g., for oligonucleotide probes) may be calculated by the formula:

T _(m)=81.5° C.+16.6(logio[Na⁺])+0.41(fraction G+C)−(600/N),

[0058] wherein N is change length and the [Na⁺] is 1 M or less. See Sambrook (1989), supra, p. 11.46. For hybridization of probes shorter than 100 nucleotides, hybridization is usually performed under stringent conditions (5-10° C. below the T_(m)) using high concentrations (0.1-1.0 pmol/ml) of probe. Id. at p. 11.45. Determination of hybridization using mismatched probes, pools of degenerate probes or “guessmers,” as well as hybridization solutions and methods for empirically determining hybridization conditions are well-known in the art. See, e.g., Ausubel (1999), supra; Sambrook (1989), supra, pp. 11.45-11.57.

[0059] The term “digestion” or “digestion of DNA” refers to catalytic cleavage of the DNA with a restriction enzyme that acts only at certain sequences in the DNA. The various restriction enzymes referred to herein are commercially available and their reaction conditions, cofactors and other requirements for use are known and routine to the skilled artisan. For analytical purposes, typically, 1 μg of plasmid or DNA fragment is digested with about 2 units of enzyme in about 20 μl of reaction buffer. For the purpose of isolating DNA fragments for plasmid construction, typically 5 to 50 μg of DNA are digested with 20 to 250 units of enzyme in proportionately larger volumes. Appropriate buffers and substrate amounts for particular restriction enzymes are described in standard laboratory manuals, such as those referenced below, and they are specified by commercial suppliers. Incubation times of about 1 hour at 37° C. are ordinarily used, but conditions may vary in accordance with standard procedures, the supplier's instructions and the particulars of the reaction. After digestion, reactions may be analyzed, and fragments may be purified by electrophoresis through an agarose or polyacrylamide gel, using well-known methods that are routine for those skilled in the art.

[0060] The term “ligation” refers to the process of forming phosphodiester bonds between two or more polynucleotides, which most often are double-stranded DNAS. Techniques for ligation are well-known to the art and protocols for ligation are described in standard laboratory manuals and references, such as, e.g., Sambrook (1989), supra.

[0061] Genome-derived “single exon probes,” are probes that comprise at least part of an exon (“reference exon”) and can hybridize detectably under high stringency conditions to transcript-derived nucleic acids that include the reference exon but do not hybridize detectably under high stringency conditions to nucleic acids that lack the reference exon. Single exon probes typically further comprise, contiguous to a first end of the exon portion, a first intronic and/or intergenic sequence that is identically contiguous to the exon in the genome, and may contain a second intronic and/or intergenic sequence that is identically contiguous to the exon in the genome. The minimum length of genome-derived single exon probes is defined by the requirement that the exonic portion be of sufficient length to hybridize under high stringency conditions to transcript-derived nucleic acids, as discussed above. The maximum length of genome-derived single exon probes is defined by the requirement that the probes contain portions of no more than one exon. The single exon probes may contain priming sequences not found in contiguity with the rest of the probe sequence in the genome, which priming sequences are useful for PCR and other amplification-based technologies.

[0062] The term “microarray” or “nucleic acid microarray” refers to a substrate-bound collection of plural nucleic acids, hybridization to each of the plurality of bound nucleic acids being separately detectable. The substrate can be solid or porous, planar or non-planar, unitary or distributed. Microarrays or nucleic acid microarrays include all the devices so called in Schena (ed.), DNA Microarrays: A Practical Approach (Practical Approach Series), Oxford University Press (1999); Nature Genet. 21(1)(suppl.): 1-60 (1999); Schena (ed.), Microarray Biochip: Tools and Technology, Eaton Publishing Company/BioTechniques Books Division (2000). These microarrays include substrate-bound collections of plural nucleic acids in which the plurality of nucleic acids are disposed on a plurality of beads, rather than on a unitary planar substrate, as is described, inter alia, in Brenner et al., Proc. Natl. Acad. Sci. USA 97(4):1665-1670 (2000).

[0063] The term “mutated” when applied to nucleic acid molecules means that nucleotides in the nucleic acid sequence of the nucleic acid molecule may be inserted, deleted or changed compared to a reference nucleic acid sequence. A single alteration may be made at a locus (a point mutation) or multiple nucleotides may be inserted, deleted or changed at a single locus. In addition, one or more alterations may be made at any number of loci within a nucleic acid sequence. In a preferred embodiment, the nucleic acid molecule comprises the wild type nucleic acid sequence encoding an LSP or is an LSNA. The nucleic acid molecule may be mutated by any method known in the art including those mutagenesis techniques described infra.

[0064] The term “error-prone PCR” refers to a process for performing PCR under conditions where the copying fidelity of the DNA polymerase is low, such that a high rate of point mutations is obtained along the entire length of the PCR product. See, e.g., Leung et al., Technique 1: 11-15 (1989) and Caldwell et al., PCR Methods Applic. 2: 28-33 (1992).

[0065] The term “oligonucleotide-directed mutagenesis” refers to a process which enables the generation of site-specific mutations in any cloned DNA segment of interest. See, e.g., Reidhaar-Olson et al., Science 241: 53-57 (1988).

[0066] The term “assembly PCR” refers to a process which involves the assembly of a PCR product from a mixture of small DNA fragments. A large number of different PCR reactions occur in parallel in the same vial, with the products of one reaction priming the products of another reaction.

[0067] The term “sexual PCR mutagenesis” or “DNA shuffling” refers to a method of error-prone PCR coupled with forced homologous recombination between DNA molecules of different but highly related DNA sequence in vitro, caused by random fragmentation of the DNA molecule based on sequence similarity, followed by fixation of the crossover by primer extension in an error-prone PCR reaction. See, e.g., Stemmer, Proc. Natl. Acad. Sci. U.S.A. 91: 10747-10751 (1994). DNA shuffling can be carried out between several related genes (“Family shuffling”).

[0068] The term “in vivo mutagenesis” refers to a process of generating random mutations in any cloned DNA of interest which involves the propagation of the DNA in a strain of bacteria such as E. coli that carries mutations in one or more of the DNA repair pathways. These “mutator” strains have a higher random mutation rate than that of a wild-type parent. Propagating the DNA in a mutator strain will eventually generate random mutations within the DNA.

[0069] The term “cassette mutagenesis” refers to any process for replacing a small region of a double-stranded DNA molecule with a synthetic oligonucleotide “cassette” that differs from the native sequence. The oligonucleotide often contains completely and/or partially randomized native sequence.

[0070] The term “recursive ensemble mutagenesis” refers to an algorithm for protein engineering (protein mutagenesis) developed to produce diverse populations of phenotypically related mutants whose members differ in amino acid sequence. This method uses a feedback mechanism to control successive rounds of combinatorial cassette mutagenesis. See, e.g., Arkin et al., Proc. Natl. Acad. Sci. U.S.A. 89: 7811-7815 (1992).

[0071] The term “exponential ensemble mutagenesis” refers to a process for generating combinatorial libraries with a high percentage of unique and functional mutants, wherein small groups of residues are randomized in parallel to identify, at each altered position, amino acids which lead to functional proteins. See, e.g., Delegrave et al., Biotechnology Research 11: 1548-1552 (1993); Arnold, Current Opinion in Biotechnology 4: 450-455 (1993). Each of the references mentioned above are hereby incorporated by reference in its entirety.

[0072] “Operatively linked” expression control sequences refers to a linkage in which the expression control sequence is contiguous with the gene of interest to control the gene of interest, as well as expression control sequences that act in trans or at a distance to control the gene of interest.

[0073] The term “expression control sequence” as used herein refers to polynucleotide sequences which are necessary to affect the expression of coding sequences to which they are operatively linked. Expression control sequences are sequences which control the transcription, post-transcriptional events and translation of nucleic acid sequences. Expression control sequences include appropriate transcription initiation, termination, promoter and enhancer sequences; efficient RNA processing signals such as splicing and polyadenylation signals; sequences that stabilize cytoplasmic mRNA; sequences that enhance translation efficiency (e.g., ribosome binding sites); sequences that enhance protein stability; and when desired, sequences that enhance protein secretion. The nature of such control sequences differs depending upon the host organism; in prokaryotes, such control sequences generally include the promoter, ribosomal binding site, and transcription termination sequence. The term “control sequences” is intended to include, at a minimum, all components whose presence is essential for expression, and can also include additional components whose presence is advantageous, for example, leader sequences and fusion partner sequences.

[0074] The term “vector,” as used herein, is intended to refer to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. One type of vector is a “plasmid”, which refers to a circular double-stranded DNA loop into which additional DNA segments may be ligated. Other vectors include cosmids, bacterial artificial chromosomes (BAC) and yeast artificial chromosomes (YAC). Another type of vector is a viral vector, wherein additional DNA segments may be ligated into the viral genome. Viral vectors that infect bacterial cells are referred to as bacteriophages. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication). Other vectors can be integrated into the genome of a host cell upon introduction into the host cell, and thereby are replicated along with the host genome. Moreover, certain vectors are capable of directing the expression of genes to which they are operatively linked. Such vectors are referred to herein as “recombinant expression vectors” (or simply, “expression vectors”). In general, expression vectors of utility in recombinant DNA techniques are often in the form of plasmids. In the present specification, “plasmid” and “vector” may be used interchangeably as the plasmid is the most commonly used form of vector. However, the invention is intended to include other forms of expression vectors that serve equivalent functions.

[0075] The term “recombinant host cell” (or simply “host cell”), as used herein, is intended to refer to a cell into which an expression vector has been introduced. It should be understood that such terms are intended to refer not only to the particular subject cell but to the progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term “host cell” as used herein.

[0076] As used herein, the phrase “open reading frame” and the equivalent acronym “ORF” refer to that portion of a transcript-derived nucleic acid that can be translated in its entirety into a sequence of contiguous amino acids. As so defined, an ORF has length, measured in nucleotides, exactly divisible by 3. As so defined, an ORF need not encode the entirety of a natural protein.

[0077] As used herein, the phrase “ORF-encoded peptide” refers to the predicted or actual translation of an ORF.

[0078] As used herein, the phrase “degenerate variant” of a reference nucleic acid sequence intends all nucleic acid sequences that can be directly translated, using the standard genetic code, to provide an amino acid sequence identical to that translated from the reference nucleic acid sequence.

[0079] The term “polypeptide” encompasses both naturally-occurring and non-naturally-occurring proteins and polypeptides, polypeptide fragments and polypeptide mutants, derivatives and analogs. A polypeptide may be monomeric or polymeric. Further, a polypeptide may comprise a number of different modules within a single polypeptide each of which has one or more distinct activities. A preferred polypeptide in accordance with the invention comprises an LSP encoded by a nucleic acid molecule of the instant invention, as well as a fragment, mutant, analog and derivative thereof.

[0080] The term “isolated protein” or “isolated polypeptide” is a protein or polypeptide that by virtue of its origin or source of derivation (1) is not associated with naturally associated components that accompany it in its native state, (2) is free of other proteins from the same species (3) is expressed by a cell from a different species, or (4) does not occur in nature. Thus, a polypeptide that is chemically synthesized or synthesized in a cellular system different from the cell from which it naturally originates will be “isolated” from its naturally associated components. A polypeptide or protein may also be rendered substantially free of naturally associated components by isolation, using protein purification techniques well-known in the art.

[0081] A protein or polypeptide is “substantially pure,” “substantially homogeneous” or “substantially purified” when at least about 60% to 75% of a sample exhibits a single species of polypeptide. The polypeptide or protein may be monomeric or multimeric. A substantially pure polypeptide or protein will typically comprise about 50%, 60%, 70%, 80% or 90% W/W of a protein sample, more usually about 95%, and preferably will be over 99% pure. Protein purity or homogeneity may be indicated by a number of means well-known in the art, such as polyacrylamide gel electrophoresis of a protein sample, followed by visualizing a single polypeptide band upon staining the gel with a stain well-known in the art. For certain purposes, higher resolution may be provided by using HPLC or other means well-known in the art for purification.

[0082] The term “polypeptide fragment” as used herein refers to a polypeptide of the instant invention that has an amino-terminal and/or carboxy-terminal deletion compared to a full-length polypeptide. In a preferred embodiment, the polypeptide fragment is a contiguous sequence in which the amino acid sequence of the fragment is identical to the corresponding positions in the naturally-occurring sequence. Fragments typically are at least 5, 6, 7, 8, 9 or 10 amino acids long, preferably at least 12, 14, 16 or 18 amino acids long, more preferably at least 20 amino acids long, more preferably at least 25, 30, 35, 40 or 45, amino acids, even more preferably at least 50 or 60 amino acids long, and even more preferably at least 70 amino acids long.

[0083] A “derivative” refers to polypeptides or fragments thereof that are substantially similar in primary structural sequence but which include, e.g., in vivo or in vitro chemical and biochemical modifications that are not found in the native polypeptide. Such modifications include, for example, acetylation, acylation, ADP-ribosylation, amidation, covalent attachment of flavin, covalent attachment of a heme moiety, covalent attachment of a nucleotide or nucleotide derivative, covalent attachment of a lipid or lipid derivative, covalent attachment of phosphotidylinositol, cross-linking, cyclization, disulfide bond formation, demethylation, formation of covalent cross-links, formation of cystine, formation of pyroglutamate, formylation, gamma-carboxylation, glycosylation, GPI anchor formation, hydroxylation, iodination, methylation, myristoylation, oxidation, proteolytic processing, phosphorylation, prenylation, racemization, selenoylation, sulfation, transfer-RNA mediated addition of amino acids to proteins such as arginylation, and ubiquitination. Other modification include, e.g., labeling with radionuclides, and various enzymatic modifications, as will be readily appreciated by those skilled in the art. A variety of methods for labeling polypeptides and of substituents or labels useful for such purposes are well-known in the art, and include radioactive isotopes such as ¹²⁵I, ³²P, ³⁵S, and ³H, ligands which bind to labeled antiligands (e.g., antibodies), fluorophores, chemiluminescent agents, enzymes, and antiligands which can serve as specific binding pair members for a labeled ligand. The choice of label depends on the sensitivity required, ease of conjugation with the primer, stability requirements, and available instrumentation. Methods for labeling polypeptides are well-known in the art. See Ausubel (1992), supra; Ausubel (1999), supra, herein incorporated by reference.

[0084] The term “fusion protein” refers to polypeptides of the instant invention comprising polypeptides or fragments coupled to heterologous amino acid sequences. Fusion proteins are useful because they can be constructed to contain two or more desired functional elements from two or more different proteins. A fusion protein comprises at least 10 contiguous amino acids from a polypeptide of interest, more preferably at least 20 or 30 amino acids, even more preferably at least 40, 50 or 60 amino acids, yet more preferably at least 75, 100 or 125 amino acids. Fusion proteins can be produced recombinantly by constructing a nucleic acid sequence which encodes the polypeptide or a fragment thereof in frame with a nucleic acid sequence encoding a different protein or peptide and then expressing the fusion protein. Alternatively, a fusion protein can be produced chemically by crosslinking the polypeptide or a fragment thereof to another protein.

[0085] The term “analog” refers to both polypeptide analogs and non-peptide analogs. The term “polypeptide analog” as used herein refers to a polypeptide of the instant invention that is comprised of a segment of at least 25 amino acids that has substantial identity to a portion of an amino acid sequence but which contains non-natural amino acids or non-natural inter-residue bonds. In a preferred embodiment, the analog has the same or similar biological activity as the native polypeptide. Typically, polypeptide analogs comprise a conservative amino acid substitution (or insertion or deletion) with respect to the naturally-occurring sequence. Analogs typically are at least 20 amino acids long, preferably at least 50 amino acids long or longer, and can often be as long as a full-length naturally-occurring polypeptide.

[0086] The term “non-peptide analog” refers to a compound with properties that are analogous to those of a reference polypeptide of the instant invention. A non-peptide compound may also be termed a “peptide mimetic” or a “peptidomimetic.” Such compounds are often developed with the aid of computerized molecular modeling. Peptide mimetics that are structurally similar to useful peptides may be used to produce an equivalent effect. Generally, peptidomimetics are structurally similar to a paradigm polypeptide (i.e., a polypeptide that has a desired biochemical property or pharmacological activity), but have one or more peptide linkages optionally replaced by a linkage selected from the group consisting of: —CH₂NH—, —CH₂S—, —CH₂—CH₂—, —CH═CH—(cis and trans), —COCH₂—, —CH(OH)CH₂—, and —CH₂SO—, by methods well-known in the art. Systematic substitution of one or more amino acids of a consensus sequence with a D-amino acid of the same type (e.g., D-lysine in place of L-lysine) may also be used to generate more stable peptides. In addition, constrained peptides comprising a consensus sequence or a substantially identical consensus sequence variation may be generated by methods known in the art (Rizo et al, Ann. Rev. Biochem. 61:387-418 (1992), incorporated herein by reference). For example, one may add internal cysteine residues capable of forming intramolecular disulfide bridges which cyclize the peptide.

[0087] A “polypeptide mutant” or “mutein” refers to a polypeptide of the instant invention whose sequence contains substitutions, insertions or deletions of one or more amino acids compared to the amino acid sequence of a native or wild-type protein. A mutein may have one or more amino acid point substitutions, in which a single amino acid at a position has been changed to another amino acid, one or more insertions and/or deletions, in which one or more amino acids are inserted or deleted, respectively, in the sequence of the naturally-occurring protein, and/or truncations of the amino acid sequence at either or both the amino or carboxy termini. Further, a mutein may have the same or different biological activity as the naturally-occurring protein. For instance, a mutein may have an increased or decreased biological activity. A mutein has at least 50% sequence similarity to the wild type protein, preferred is 60% sequence similarity, more preferred is 70% sequence similarity. Even more preferred are muteins having 80%, 85% or 90% sequence similarity to the wild type protein. In an even more preferred embodiment, a mutein exhibits 95% sequence identity, even more preferably 97%, even more preferably 98% and even more preferably 99%. Sequence similarity may be measured by any common sequence analysis algorithm, such as Gap or Bestfit.

[0088] Preferred amino acid substitutions are those which: (1) reduce susceptibility to proteolysis, (2) reduce susceptibility to oxidation, (3) alter binding affinity for forming protein complexes, (4) alter binding affinity or enzymatic activity, and (5) confer or modify other physicochemical or functional properties of such analogs. For example, single or multiple amino acid substitutions (preferably conservative amino acid substitutions) may be made in the naturally-occurring sequence (preferably in the portion of the polypeptide outside the domain(s) forming intermolecular contacts. In a preferred embodiment, the amino acid substitutions are moderately conservative substitutions or conservative substitutions. In a more preferred embodiment, the amino acid substitutions are conservative substitutions. A conservative amino acid substitution should not substantially change the structural characteristics of the parent sequence (e.g., a replacement amino acid should not tend to disrupt a helix that occurs in the parent sequence, or disrupt other types of secondary structure that characterizes the parent sequence). Examples of art-recognized polypeptide secondary and tertiary structures are described in Creighton (ed.), Proteins, Structures and Molecular Principles, W. H. Freeman and Company (1984); Branden et al. (ed.), Introduction to Protein Structure, Garland Publishing (1991); Thornton et al., Nature 354:105-106 (1991), each of which are incorporated herein by reference.

[0089] As used herein, the twenty conventional amino acids and their abbreviations follow conventional usage. See Golub et al. (eds.), Immunology—A Synthesis 2^(nd) Ed., Sinauer Associates (1991), which is incorporated herein by reference. Stereoisomers (e.g., D-amino acids) of the twenty conventional amino acids, unnatural amino acids such as -, -disubstituted amino acids, N-alkyl amino acids, and other unconventional amino acids may also be suitable components for polypeptides of the present invention. Examples of unconventional amino acids include: 4-hydroxyproline, γ-carboxyglutamate, -N,N,N-trimethyllysine, -N-acetyllysine, O-phosphoserine, N-acetylserine, N-formylmethionine, 3-methylhistidine, 5-hydroxylysine, s-N-methylarginine, and other similar amino acids and imino acids (e.g., 4-hydroxyproline). In the polypeptide notation used herein, the lefthand direction is the amino terminal direction and the right hand direction is the carboxy-terminal direction, in accordance with standard usage and convention.

[0090] A protein has “homology” or is “homologous” to a protein from another organism if the encoded amino acid sequence of the protein has a similar sequence to the encoded amino acid sequence of a protein of a different organism and has a similar biological activity or function. Alternatively, a protein may have homology or be homologous to another protein if the two proteins have similar amino acid sequences and have similar biological activities or functions. Although two proteins are said to be “homologous,” this does not imply that there is necessarily an evolutionary relationship between the proteins. Instead, the term “homologous” is defined to mean that the two proteins have similar amino acid sequences and similar biological activities or functions. In a preferred embodiment, a homologous protein is one that exhibits 50% sequence similarity to the wild type protein, preferred is 60% sequence similarity, more preferred is 70% sequence similarity. Even more preferred are homologous proteins that exhibit 80%, 85% or 90% sequence similarity to the wild type protein. In a yet more preferred embodiment, a homologous protein exhibits 95%, 97%, 98% or 99% sequence similarity.

[0091] When “sequence similarity” is used in reference to proteins or peptides, it is recognized that residue positions that are not identical often differ by conservative amino acid substitutions. In a preferred embodiment, a polypeptide that has “sequence similarity” comprises conservative or moderately conservative amino acid substitutions. A “conservative amino acid substitution” is one in which an amino acid residue is substituted by another amino acid residue having a side chain (R group) with similar chemical properties (e.g., charge or hydrophobicity). In general, a conservative amino acid substitution will not substantially change the functional properties of a protein. In cases where two or more amino acid sequences differ from each other by conservative substitutions, the percent sequence identity or degree of similarity may be adjusted upwards to correct for the conservative nature of the substitution. Means for making this adjustment are well-known to those of skill in the art. See, e.g., Pearson, Methods Mol. Biol. 24: 307-31 (1994), herein incorporated by reference.

[0092] For instance, the following six groups each contain amino acids that are conservative substitutions for one another:

[0093] 1) Serine (S), Threonine (T);

[0094] 2) Aspartic Acid (D), Glutamic Acid (E);

[0095] 3) Asparagine (N), Glutamine (Q);

[0096] 4) Arginine (R), Lysine (K);

[0097] 5) Isoleucine (I), Leucine (L), Methionine (M), Alanine (A), Valine (V), and

[0098] 6) Phenylalanine (F), Tyrosine (Y), Tryptophan (W).

[0099] Alternatively, a conservative replacement is any change having a positive value in the PAM250 log-likelihood matrix disclosed in Gonnet et al., Science 256: 1443-45 (1992), herein incorporated by reference. A “moderately conservative” replacement is any change having a nonnegative value in the PAM250 log-likelihood matrix.

[0100] Sequence similarity for polypeptides, which is also referred to as sequence identity, is typically measured using sequence analysis software. Protein analysis software matches similar sequences using measures of similarity assigned to various substitutions, deletions and other modifications, including conservative amino acid substitutions. For instance, GCG contains programs such as “Gap” and “Bestfit” which can be used with default parameters to determine sequence homology or sequence identity between closely related polypeptides, such as homologous polypeptides from different species of organisms or between a wild type protein and a mutein thereof. See, e.g., GCG Version 6.1. Other programs include FASTA, discussed supra.

[0101] A preferred algorithm when comparing a sequence of the invention to a database containing a large number of sequences from different organisms is the computer program BLAST, especially blastp or tblastn. See, e.g., Altschul et al., J. Mol. Biol. 215: 403-410 (1990); Altschul et al., Nucleic Acids Res. 25:3389-402 (1997); herein incorporated by reference. Preferred parameters for blastp are: Expectation value:  10 (default) Filter: seg (default) Cost to open a gap:  11 (default) Cost to extend a gap:  1 (default Max. alignments: 100 (default) Word size:  11 (default) No. of descriptions: 100 (default) Penalty Matrix: BLOSUM62

[0102] The length of polypeptide sequences compared for homology will generally be at least about 16 amino acid residues, usually at least about 20 residues, more usually at least about 24 residues, typically at least about 28 residues, and preferably more than about 35 residues. When searching a database containing sequences from a large number of different organisms, it is preferable to compare amino acid sequences.

[0103] Database searching using amino acid sequences can be measured by algorithms other than blastp are known in the art. For instance, polypeptide sequences can be compared using FASTA, a program in GCG Version 6.1. FASTA (e.g., FASTA2 and FASTA3) provides alignments and percent sequence identity of the regions of the best overlap between the query and search sequences (Pearson (1990), supra; Pearson (2000), supra. For example, percent sequence identity between amino acid sequences can be determined using FASTA with its default or recommended parameters (a word size of 2 and the PAM250 scoring matrix), as provided in GCG Version 6.1, herein incorporated by reference.

[0104] An “antibody” refers to an intact immunoglobulin, or to an antigen-binding portion thereof that competes with the intact antibody for specific binding to a molecular species, e.g., a polypeptide of the instant invention. Antigen-binding portions may be produced by recombinant DNA techniques or by enzymatic or chemical cleavage of intact antibodies. Antigen-binding portions include, inter alia, Fab, Fab′, F(ab′)₂, Fv, dAb, and complementarity determining region (CDR) fragments, single-chain antibodies (scFv), chimeric antibodies, diabodies and polypeptides that contain at least a portion of an immunoglobulin that is sufficient to confer specific antigen binding to the polypeptide. An Fab fragment is a monovalent fragment consisting of the VL, VH, CL and CH1 domains; an F(ab′)₂ fragment is a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; an Fd fragment consists of the VH and CHI domains; an Fv fragment consists of the VL and VH domains of a single arm of an antibody; and a dAb fragment consists of a VH domain. See, e.g., Ward et al., Nature 341: 544-546 (1989).

[0105] By “bind specifically” and “specific binding” is here intended the ability of the antibody to bind to a first molecular species in preference to binding to other molecular species with which the antibody and first molecular species are admixed. An antibody is said specifically to “recognize” a first molecular species when it can bind specifically to that first molecular species.

[0106] A single-chain antibody (scFv) is an antibody in which a VL and VH region are paired to form a monovalent molecule via a synthetic linker that enables them to be made as a single protein chain. See, e.g., Bird et al., Science 242: 423-426 (1988); Huston et al., Proc. Natl. Acad. Sci. USA 85: 5879-5883 (1988). Diabodies are bivalent, bispecific antibodies in which VH and VL domains are expressed on a single polypeptide chain, but using a linker that is too short to allow for pairing between the two domains on the same chain, thereby forcing the domains to pair with complementary domains of another chain and creating two antigen binding sites. See e.g., Holliger et al., Proc. Natl. Acad. Sci. USA 90: 6444-6448 (1993); Poljak et al., Structure 2: 1121-1123 (1994). One or more CDRs may be incorporated into a molecule either covalently or noncovalently to make it an immunoadhesin. An immunoadhesin may incorporate the CDR(s) as part of a larger polypeptide chain, may covalently link the CDR(s) to another polypeptide chain, or may incorporate the CDR(s) noncovalently. The CDRs permit the immunoadhesin to specifically bind to a particular antigen of interest. A chimeric antibody is an antibody that contains one or more regions from one antibody and one or more regions from one or more other antibodies.

[0107] An antibody may have one or more binding sites. If there is more than one binding site, the binding sites may be identical to one another or may be different. For instance, a naturally-occurring immunoglobulin has two identical binding sites, a single-chain antibody or Fab fragment has one binding site, while a “bispecific” or “bifunctional” antibody has two different binding sites.

[0108] An “isolated antibody” is an antibody that (1) is not associated with naturally-associated components, including other naturally-associated antibodies, that accompany it in its native state, (2) is free of other proteins from the same species, (3) is expressed by a cell from a different species, or (4) does not occur in nature. It is known that purified proteins, including purified antibodies, may be stabilized with non-naturally-associated components. The non-naturally-associated component may be a protein, such as albumin (e.g., BSA) or a chemical such as polyethylene glycol (PEG).

[0109] A “neutralizing antibody” or “an inhibitory antibody” is an antibody that inhibits the activity of a polypeptide or blocks the binding of a polypeptide to a ligand that normally binds to it. An “activating antibody” is an antibody that increases the activity of a polypeptide.

[0110] The term “epitope” includes any protein determinant capable of specifically binding to an immunoglobulin or T-cell receptor. Epitopic determinants usually consist of chemically active surface groupings of molecules such as amino acids or sugar side chains and usually have specific three-dimensional structural characteristics, as well as specific charge characteristics. An antibody is said to specifically bind an antigen when the dissociation constant is less than 1 μM, preferably less than 100 nM and most preferably less than 10 nM.

[0111] The term “patient” as used herein includes human and veterinary subjects.

[0112] Throughout this specification and claims, the word “comprise,” or variations such as “comprises” or “comprising,” will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

[0113] The term “lung specific” refers to a nucleic acid molecule or polypeptide that is expressed predominantly in the lung as compared to other tissues in the body. In a preferred embodiment, a “lung specific” nucleic acid molecule or polypeptide is expressed at a level that is 5-fold higher than any other tissue in the body. In a more preferred embodiment, the “lung specific” nucleic acid molecule or polypeptide is expressed at a level that is 10-fold higher than any other tissue in the body, more preferably at least 15-fold, 20-fold, 25-fold, 50-fold or 100-fold higher than any other tissue in the body. Nucleic acid molecule levels may be measured by nucleic acid hybridization, such as Northern blot hybridization, or quantitative PCR. Polypeptide levels may be measured by any method known to accurately quantitate protein levels, such as Western blot analysis.

[0114] Nucleic Acid Molecules, Regulatory Sequences, Vectors, Host Cells and Recombinant Methods of Making Polypeptides

[0115] Nucleic Acid Molecules

[0116] One aspect of the invention provides isolated nucleic acid molecules that are specific to the lung or to lung cells or tissue or that are derived from such nucleic acid molecules. These isolated lung specific nucleic acids (LSNAs) may comprise a cDNA, a genomic DNA, RNA, or a fragment of one of these nucleic acids, or may be a non-naturally-occurring nucleic acid molecule. In a preferred embodiment, the nucleic acid molecule encodes a polypeptide that is specific to lung, a lung-specific polypeptide (LSP). In a more preferred embodiment, the nucleic acid molecule encodes a polypeptide that comprises an amino acid sequence of SEQ ID NO: 165 through 284. In another highly preferred embodiment, the nucleic acid molecule comprises a nucleic acid sequence of SEQ ID NO: 1 through 164.

[0117] An LSNA may be derived from a human or from another animal. In a preferred embodiment, the LSNA is derived from a human or other mammal. In a more preferred embodiment, the LSNA is derived from a human or other primate. In an even more preferred embodiment, the LSNA is derived from a human.

[0118] By “nucleic acid molecule” for purposes of the present invention, it is also meant to be inclusive of nucleic acid sequences that selectively hybridize to a nucleic acid molecule encoding an LSNA or a complement thereof. The hybridizing nucleic acid molecule may or may not encode a polypeptide or may not encode an LSP. However, in a preferred embodiment, the hybridizing nucleic acid molecule encodes an LSP. In a more preferred embodiment, the invention provides a nucleic acid molecule that selectively hybridizes to a nucleic acid molecule that encodes a polypeptide comprising an amino acid sequence of SEQ ID NO: 165 through 284. In an even more preferred embodiment, the invention provides a nucleic acid molecule that selectively hybridizes to a nucleic acid molecule comprising the nucleic acid sequence of SEQ ID NO: 1 through 164.

[0119] In a preferred embodiment, the nucleic acid molecule selectively hybridizes to a nucleic acid molecule encoding an LSP under low stringency conditions. In a more preferred embodiment, the nucleic acid molecule selectively hybridizes to a nucleic acid molecule encoding an LSP under moderate stringency conditions. In a more preferred embodiment, the nucleic acid molecule selectively hybridizes to a nucleic acid molecule encoding an LSP under high stringency conditions. In an even more preferred embodiment, the nucleic acid molecule hybridizes under low, moderate or high stringency conditions to a nucleic acid molecule encoding a polypeptide comprising an amino acid sequence of SEQ ID NO: 165 through 284. In a yet more preferred embodiment, the nucleic acid molecule hybridizes under low, moderate or high stringency conditions to a nucleic acid molecule comprising a nucleic acid sequence selected from SEQ ID NO: 1 through 164. In a preferred embodiment of the invention, the hybridizing nucleic acid molecule may be used to express recombinantly a polypeptide of the invention.

[0120] By “nucleic acid molecule” as used herein it is also meant to be inclusive of sequences that exhibits substantial sequence similarity to a nucleic acid encoding an LSP or a complement of the encoding nucleic acid molecule. In a preferred embodiment, the nucleic acid molecule exhibits substantial sequence similarity to a nucleic acid molecule encoding human LSP. In a more preferred embodiment, the nucleic acid molecule exhibits substantial sequence similarity to a nucleic acid molecule encoding a polypeptide having an amino acid sequence of SEQ ID NO: 165 through 284. In a preferred embodiment, the similar nucleic acid molecule is one that has at least 60% sequence identity with a nucleic acid molecule encoding an LSP, such as a polypeptide having an amino acid sequence of SEQ ID NO: 165 through 284, more preferably at least 70%, even more preferably at least 80% and even more preferably at least 85%. In a more preferred embodiment, the similar nucleic acid molecule is one that has at least 90% sequence identity with a nucleic acid molecule encoding an LSP, more preferably at least 95%, more preferably at least 97%, even more preferably at least 98%, and still more preferably at least 99%. In another highly preferred embodiment, the nucleic acid molecule is one that has at least 99.5%, 99.6%, 99.7%, 99.8% or 99.9% sequence identity with a nucleic acid molecule encoding an LSP.

[0121] In another preferred embodiment, the nucleic acid molecule exhibits substantial sequence similarity to an LSNA or its complement. In a more preferred embodiment, the nucleic acid molecule exhibits substantial sequence similarity to a nucleic acid molecule comprising a nucleic acid sequence of SEQ ID NO: 1 through 164. In a preferred embodiment, the nucleic acid molecule is one that has at least 60% sequence identity with an LSNA, such as one having a nucleic acid sequence of SEQ ID NO: 1 through 164, more preferably at least 70%, even more preferably at least 80% and even more preferably at least 85%. In a more preferred embodiment, the nucleic acid molecule is one that has at least 90% sequence identity with an LSNA, more preferably at least 95%, more preferably at least 97%, even more preferably at least 98%, and still more preferably at least 99%. In another highly preferred embodiment, the nucleic acid molecule is one that has at least 99.5%, 99.6%, 99.7%, 99.8% or 99.9% sequence identity with an LSNA.

[0122] A nucleic acid molecule that exhibits substantial sequence similarity may be one that exhibits sequence identity over its entire length to an LSNA or to a nucleic acid molecule encoding an LSP, or may be one that is similar over only a part of its length. In this case, the part is at least 50 nucleotides of the LSNA or the nucleic acid molecule encoding an LSP, preferably at least 100 nucleotides, more preferably at least 150 or 200 nucleotides, even more preferably at least 250 or 300 nucleotides, still more preferably at least 400 or 500 nucleotides.

[0123] The substantially similar nucleic acid molecule may be a naturally-occurring one that is derived from another species, especially one derived from another primate, wherein the similar nucleic acid molecule encodes an amino acid sequence that exhibits significant sequence identity to that of SEQ ID NO: 165 through 284 or demonstrates significant sequence identity to the nucleotide sequence of SEQ ID NO: 1 through 164. The similar nucleic acid molecule may also be a naturally-occurring nucleic acid molecule from a human, when the LSNA is a member of a gene family. The similar nucleic acid molecule may also be a naturally-occurring nucleic acid molecule derived from a non-primate, mammalian species, including without limitation, domesticated species, e.g., dog, cat, mouse, rat, rabbit, hamster, cow, horse and pig; and wild animals, e.g., monkey, fox, lions, tigers, bears, giraffes, zebras, etc. The substantially similar nucleic acid molecule may also be a naturally-occurring nucleic acid molecule derived from a non-mammalian species, such as birds or reptiles. The naturally-occurring substantially similar nucleic acid molecule may be isolated directly from humans or other species. In another embodiment, the substantially similar nucleic acid molecule may be one that is experimentally produced by random mutation of a nucleic acid molecule. In another embodiment, the substantially similar nucleic acid molecule may be one that is experimentally produced by directed mutation of an LSNA. Further, the substantially similar nucleic acid molecule may or may not be an LSNA. However, in a preferred embodiment, the substantially similar nucleic acid molecule is an LSNA.

[0124] By “nucleic acid molecule” it is also meant to be inclusive of allelic variants of an LSNA or a nucleic acid encoding an LSP. For instance, single nucleotide polymorphisms (SNPs) occur frequently in eukaryotic genomes. In fact, more than 1.4 million SNPs have already identified in the human genome, International Human Genome Sequencing Consortium, Nature 409: 860-921 (2001). Thus, the sequence determined from one individual of a species may differ from other allelic forms present within the population. Additionally, small deletions and insertions, rather than single nucleotide polymorphisms, are not uncommon in the general population, and often do not alter the function of the protein. Further, amino acid substitutions occur frequently among natural allelic variants, and often do not substantially change protein function.

[0125] In a preferred embodiment, the nucleic acid molecule comprising an allelic variant is a variant of a gene, wherein the gene is transcribed into an mRNA that encodes an LSP. In a more preferred embodiment, the gene is transcribed into an mRNA that encodes an LSP comprising an amino acid sequence of SEQ ID NO: 165 through 284. In another preferred embodiment, the allelic variant is a variant of a gene, wherein the gene is transcribed into an mRNA that is an LSNA. In a more preferred embodiment, the gene is transcribed into an mRNA that comprises the nucleic acid sequence of SEQ ID NO: 1 through 164. In a preferred embodiment, the allelic variant is a naturally-occurring allelic variant in the species of interest. In a more preferred embodiment, the species of interest is human.

[0126] By “nucleic acid molecule” it is also meant to be inclusive of a part of a nucleic acid sequence of the instant invention. The part may or may not encode a polypeptide, and may or may not encode a polypeptide that is an LSP. However, in a preferred embodiment, the part encodes an LSP. In one aspect, the invention comprises a part of an LSNA. In a second aspect, the invention comprises a part of a nucleic acid molecule that hybridizes or exhibits substantial sequence similarity to an LSNA. In a third aspect, the invention comprises a part of a nucleic acid molecule that is an allelic variant of an LSNA. In a fourth aspect, the invention comprises a part of a nucleic acid molecule that encodes an LSP. A part comprises at least 10 nucleotides, more preferably at least 15, 17, 18, 20, 25, 30, 35, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400 or 500 nucleotides. The maximum size of a nucleic acid part is one nucleotide shorter than the sequence of the nucleic acid molecule encoding the full-length protein.

[0127] By “nucleic acid molecule” it is also meant to be inclusive of sequence that encoding a fusion protein, a homologous protein, a polypeptide fragment, a mutein or a polypeptide analog, as described below.

[0128] Nucleotide sequences of the instantly-described nucleic acids were determined by sequencing a DNA molecule that had resulted, directly or indirectly, from at least one enzymatic polymerization reaction (e.g., reverse transcription and/or polymerase chain reaction) using an automated sequencer (such as the MegaBACE™ 1000, Molecular Dynamics, Sunnyvale, Calif., USA). Further, all amino acid sequences of the polypeptides of the present invention were predicted by translation from the nucleic acid sequences so determined, unless otherwise specified.

[0129] In a preferred embodiment of the invention, the nucleic acid molecule contains modifications of the native nucleic acid molecule. These modifications include nonnative intemucleoside bonds, post-synthetic modifications or altered nucleotide analogues. One having ordinary skill in the art would recognize that the type of modification that can be made will depend upon the intended use of the nucleic acid molecule. For instance, when the nucleic acid molecule is used as a hybridization probe, the range of such modifications will be limited to those that permit sequence-discriminating base pairing of the resulting nucleic acid. When used to direct expression of RNA or protein in vitro or in vivo, the range of such modifications will be limited to those that permit the nucleic acid to function properly as a polymerization substrate. When the isolated nucleic acid is used as a therapeutic agent, the modifications will be limited to those that do not confer toxicity upon the isolated nucleic acid.

[0130] In a preferred embodiment, isolated nucleic acid molecules can include nucleotide analogues that incorporate labels that are directly detectable, such as radiolabels or fluorophores, or nucleotide analogues that incorporate labels that can be visualized in a subsequent reaction, such as biotin or various haptens. In a more preferred embodiment, the labeled nucleic acid molecule may be used as a hybridization probe.

[0131] Common radiolabeled analogues include those labeled with ³³P, ³²P, and 35S, such as -³²P-dATP, -³²P-dCTP, -³²P-dGTP, -³²P-dTTP, ³²P-3′dATP, ³²P-ATP, -³²P-CTP, -³²P-GTP, ³²P-UTP, α-³⁵S-dATP, α-³⁵S-GTP, α-³³P-dATP, and the like.

[0132] Commercially available fluorescent nucleotide analogues readily incorporated into the nucleic acids of the present invention include Cy3-dCTP, Cy3-dUTP, Cy5-dCTP, Cy3-dUTP (Amersham Pharmacia Biotech, Piscataway, New Jersey, USA), fluorescein-12-dUTP, tetramethylrhodamine-6-dUTP, Texas Red®-5-dUTP, Cascade Blue®-7-dUTP, BODIPY® FL-14-dUTP, BODIPY® TMR-14-dUTP, BODIPY® TR-14-dUTP, Rhodamine Green™-5-dUTP, Oregon Green® 488-5-dUTP, Texas Red®-12-dUTP, BODIPY® 630/650-14-dUTP, BODIPY® 650/665-14-dUTP, Alexa Fluor® 488-5-dUTP, Alexa Fluor® 532-5-dUTP, Alexa Fluor® 568-5-dUTP, Alexa Fluorg 594-5-dUTP, Alexa Fluor® 546-14-dUTP, fluorescein-12-UTP, tetramethylrhodamine-6-UTP, Texas Red®-5-UTP, Cascade Blue®-7-UTP, BODIPY® FL-14-UTP, BODIPY® TMR-14-UTP, BODIPY® TR-14-UTP, Rhodamine Green™-5-UTP, Alexa Fluor® 488-5-UTP, Alexa Fluor® 546-14-UTP (Molecular Probes, Inc. Eugene, Oreg., USA). One may also custom synthesize nucleotides having other fluorophores. See Henegariu et al., Nature Biotechnol. 18: 345-348 (2000), the disclosure of which is incorporated herein by reference in its entirety.

[0133] Haptens that are commonly conjugated to nucleotides for subsequent labeling include biotin (biotin-11-dUTP, Molecular Probes, Inc., Eugene, Oreg., USA; biotin-21-UTP, biotin-21-dUTP, Clontech Laboratories, Inc., Palo Alto, Calif., USA), digoxigenin (DIG-11-dUTP, alkali labile, DIG-11-UTP, Roche Diagnostics Corp., Indianapolis, Ind., USA), and dinitrophenyl (dinitrophenyl-11-dUTP, Molecular Probes, Inc., Eugene, Oreg., USA).

[0134] Nucleic acid molecules can be labeled by incorporation of labeled nucleotide analogues into the nucleic acid. Such analogues can be incorporated by enzymatic polymerization, such as by nick translation, random priming, polymerase chain reaction (PCR), terminal transferase tailing, and end-filling of overhangs, for DNA molecules, and in vitro transcription driven, e.g., from phage promoters, such as T7, T3, and SP6, for RNA molecules. Commercial kits are readily available for each such labeling approach. Analogues can also be incorporated during automated solid phase chemical synthesis. Labels can also be incorporated after nucleic acid synthesis, with the 5′ phosphate and 3′ hydroxyl providing convenient sites for post-synthetic covalent attachment of detectable labels.

[0135] Other post-synthetic approaches also permit internal labeling of nucleic acids. For example, fluorophores can be attached using a cisplatin reagent that reacts with the N7 of guanine residues (and, to a lesser extent, adenine bases) in DNA, RNA, and PNA to provide a stable coordination complex between the nucleic acid and fluorophore label (Universal Linkage System) (available from Molecular Probes, Inc., Eugene, Oreg., USA and Amersham Pharmacia Biotech, Piscataway, N.J., USA); see Alers et al., Genes, Chromosomes & Cancer 25: 301-305 (1999); Jelsma et al., J. NIH Res. 5: 82 (1994); Van Belkum et al., BioTechniques 16: 148-153 (1994), incorporated herein by reference. As another example, nucleic acids can be labeled using a disulfide-containing linker (FastTag™ Reagent, Vector Laboratories, Inc., Burlingame, Calif., USA) that is photo- or thermally-coupled to the target nucleic acid using aryl azide chemistry; after reduction, a free thiol is available for coupling to a hapten, fluorophore, sugar, affinity ligand, or other marker.

[0136] One or more independent or interacting labels can be incorporated into the nucleic acid molecules of the present invention. For example, both a fluorophore and a moiety that in proximity thereto acts to quench fluorescence can be included to report specific hybridization through release of fluorescence quenching or to report exonucleotidic excision. See, e.g., Tyagi et al., Nature Biotechnol. 14: 303-308 (1996); Tyagi et al., Nature Biotechnol. 16: 49-53 (1998); Sokol et al., Proc. Natl. Acad. Sci. USA 95: 11538-11543 (1998); Kostrikis et al., Science 279: 1228-1229 (1998); Marras et al., Genet. Anal. 14: 151-156 (1999); U.S. Pat. Nos. 5,846,726; 5,925,517; 5,925,517; 5,723,591 and 5,538,848; Holland et al., Proc. Natl. Acad. Sci. USA 88: 7276-7280 (1991); Heid et al., Genome Res. 6(10): 986-94 (1996); Kuimelis et al., Nucleic Acids Symp. Ser. (37): 255-6 (1997); the disclosures of which are incorporated herein by reference in their entireties.

[0137] Nucleic acid molecules of the invention may be modified by altering one or more native phosphodiester internucleoside bonds to more nuclease-resistant, internucleoside bonds. See Hartmann et al. (eds.), Manual of Antisense Methodology: Perspectives in Antisense Science, Kluwer Law International (1999); Stein et al. (eds.), Applied Antisense Oligonucleotide Technology, Wiley-Liss (1998); Chadwick et al. (eds.), Oligonucleotides as Therapeutic Agents—Symposium No. 209, John Wiley & Son Ltd (1997); the disclosures of which are incorporated herein by reference in their entireties. Such altered intemucleoside bonds are often desired for antisense techniques or for targeted gene correction. See Gamper et al., Nucl. Acids Res. 28(21): 4332-4339 (2000), the disclosure of which is incorporated herein by reference in its entirety.

[0138] Modified oligonucleotide backbones include, without limitation, phosphorothioates, chiral phosphorothioates, phosphorodithioates, phosphotriesters, aminoalkylphosphotriesters, methyl and other alkyl phosphonates including 3′-alkylene phosphonates and chiral phosphonates, phosphinates, phosphoramidates including 3′-amino phosphoramidate and aminoalkylphosphoramidates, thionophosphoramidates, thionoalkylphosphonates, thionoalkylphosphotriesters, and boranophosphates having normal 3′-5′ linkages, 2′-5′ linked analogs of these, and those having inverted polarity wherein the adjacent pairs of nucleoside units are linked 3′-5′ to 5′-3′ or 2′-5′ to 5′-2′. Representative United States patents that teach the preparation of the above phosphorus-containing linkages include, but are not limited to, U.S. Pat. Nos. 3,687,808; 4,469,863; 4,476,301; 5,023,243; 5,177,196; 5,188,897; 5,264,423; 5,276,019; 5,278,302; 5,286,717; 5,321,131; 5,399,676; 5,405,939; 5,453,496; 5,455,233; 5,466,677; 5,476,925; 5,519,126; 5,536,821; 5,541,306; 5,550,111; 5,563,253; 5,571,799; 5,587,361; and 5,625,050, the disclosures of which are incorporated herein by reference in their entireties. In a preferred embodiment, the modified internucleoside linkages may be used for antisense techniques.

[0139] Other modified oligonucleotide backbones do not include a phosphorus atom, but have backbones that are formed by short chain alkyl or cycloalkyl internucleoside linkages, mixed heteroatom and alkyl or cycloalkyl internucleoside linkages, or one or more short chain heteroatomic or heterocyclic intemucleoside linkages. These include those having morpholino linkages (formed in part from the sugar portion of a nucleoside); siloxane backbones; sulfide, sulfoxide and sulfone backbones; formacetyl and thioformacetyl backbones; methylene formacetyl and thioformacetyl backbones; alkene containing backbones; sulfamate backbones; methyleneimino and methylenehydrazino backbones; sulfonate and sulfonamide backbones; amide backbones; and others having mixed N, O, S and CH₂ component parts. Representative U.S. patents that teach the preparation of the above backbones include, but are not limited to, U.S. Pat. Nos. 5,034,506; 5,166,315; 5,185,444; 5,214,134; 5,216,141; 5,235,033; 5,264,562; 5,264,564; 5,405,938; 5,434,257; 5,466,677; 5,470,967; 5,489,677; 5,541,307; 5,561,225; 5,596,086; 5,602,240; 5,610,289; 5,602,240; 5,608,046; 5,610,289; 5,618,704; 5,623,070; 5,663,312; 5,633,360; 5,677,437 and 5,677,439; the disclosures of which are incorporated herein by reference in their entireties.

[0140] In other preferred oligonucleotide mimetics, both the sugar and the intemucleoside linkage are replaced with novel groups, such as peptide nucleic acids (PNA). In PNA compounds, the phosphodiester backbone of the nucleic acid is replaced with an amide-containing backbone, in particular by repeating N-(2-aminoethyl) glycine units linked by arnide bonds. Nucleobases are bound directly or indirectly to aza nitrogen atoms of the amide portion of the backbone, typically by methylene carbonyl linkages. PNA can be synthesized using a modified peptide synthesis protocol. PNA oligomers can be synthesized by both Fmoc and tBoc methods. Representative U.S. patents that teach the preparation of PNA compounds include, but are not limited to, U.S. Pat. Nos. 5,539,082; 5,714,331; and 5,719,262, each of which is herein incorporated by reference. Automated PNA synthesis is readily achievable on commercial synthesizers (see, e.g., “PNA User's Guide,” Rev. 2, February 1998, Perseptive Biosystems Part No. 60138, Applied Biosystems, Inc., Foster City, Calif.).

[0141] PNA molecules are advantageous for a number of reasons. First, because the PNA backbone is uncharged, PNA/DNA and PNA/RNA duplexes have a higher thermal stability than is found in DNA/DNA and DNA/RNA duplexes. The Tm of a PNA/DNA or PNA/RNA duplex is generally 1° C. higher per base pair than the Tm of the corresponding DNA/DNA or DNA/RNA duplex (in 100 mM NaCl). Second, PNA molecules can also form stable PNA/DNA complexes at low ionic strength, under conditions in which DNA/DNA duplex formation does not occur. Third, PNA also demonstrates greater specificity in binding to complementary DNA because a PNA/DNA mismatch is more destabilizing than DNA/DNA mismatch. A single mismatch in mixed a PNA/DNA 15-mer lowers the Tm by 8-20° C. (15° C. on average). In the corresponding DNA/DNA duplexes, a single mismatch lowers the Tm by 4-16° C. (1°° C. on average). Because PNA probes can be significantly shorter than DNA probes, their specificity is greater. Fourth, PNA oligomers are resistant to degradation by enzymes, and the lifetime of these compounds is extended both in vivo and in vitro because nucleases and proteases do not recognize the PNA polyamide backbone with nucleobase sidechains. See, e.g., Ray et al, FASEB J. 14(9): 1041-60 (2000); Nielsen et al., Pharmacol Toxicol. 86(1): 3-7 (2000); Larsen et al., Biochim Biophys Acta. 1489(1): 159-66 (1999); Nielsen, Curr. Opin. Struct. Biol. 9(3): 353-7 (1999), and Nielsen, Curr. Opin. Biotechnol. 10(1): 71-5 (1999), the disclosures of which are incorporated herein by reference in their entireties.

[0142] Nucleic acid molecules may be modified compared to their native structure throughout the length of the nucleic acid molecule or can be localized to discrete portions thereof. As an example of the latter, chimeric nucleic acids can be synthesized that have discrete DNA and RNA domains and that can be used for targeted gene repair and modified PCR reactions, as further described in U.S. Pat. Nos. 5,760,012 and 5,731,181, Misra et al, Biochem. 37: 1917-1925 (1998); and Finn et al, Nucl. Acids Res. 24: 3357-3363 (1996), the disclosures of which are incorporated herein by reference in their entireties.

[0143] Unless otherwise specified, nucleic acids of the present invention can include any topological conformation appropriate to the desired use; the term thus explicitly comprehends, among others, single-stranded, double-stranded, triplexed, quadruplexed, partially double-stranded, partially-triplexed, partially-quadruplexed, branched, hairpinned, circular, and padlocked conformations. Padlock conformations and their utilities are further described in Banér et al., Curr. Opin. Biotechnol. 12: 11-15 (2001); Escude et al., Proc. Natl. Acad. Sci. USA 14: 96(19):10603-7 (1999); Nilsson et al., Science 265(5181): 2085-8 (1994), the disclosures of which are incorporated herein by reference in their entireties. Triplex and quadruplex conformations, and their utilities, are reviewed in Praseuth et al., Biochim. Biophys. Acta. 1489(1): 181-206 (1999); Fox, Curr. Med. Chem. 7(1): 17-37 (2000); Kochetkova et al., Methods Mol. Biol. 130: 189-201 (2000); Chan et al., J. Mol. Med. 75(4): 267-82 (1997), the disclosures of which are incorporated herein by reference in their entireties.

[0144] Methods for Using Nucleic Acid Molecules as Probes and Primers

[0145] The isolated nucleic acid molecules of the present invention can be used as hybridization probes to detect, characterize, and quantify hybridizing nucleic acids in, and isolate hybridizing nucleic acids from, both genomic and transcript-derived nucleic acid samples. When free in solution, such probes are typically, but not invariably, detectably labeled; bound to a substrate, as in a microarray, such probes are typically, but not invariably unlabeled.

[0146] In one embodiment, the isolated nucleic acids of the present invention can be used as probes to detect and characterize gross alterations in the gene of an LSNA, such as deletions, insertions, translocations, and duplications of the LSNA genomic locus through fluorescence in situ hybridization (FISH) to chromosome spreads. See, e.g., Andreeff et al. (eds.), Introduction to Fluorescence In Situ Hybridization: Principles and Clinical Applications, John Wiley & Sons (1999), the disclosure of which is incorporated herein by reference in its entirety. The isolated nucleic acids of the present invention can be used as probes to assess smaller genomic alterations using, e.g., Southern blot detection of restriction fragment length polymorphisms. The isolated nucleic acid molecules of the present invention can be used as probes to isolate genomic clones that include the nucleic acid molecules of the present invention, which thereafter can be restriction mapped and sequenced to identify deletions, insertions, translocations, and substitutions (single nucleotide polymorphisms, SNPs) at the sequence level.

[0147] In another embodiment, the isolated nucleic acid molecules of the present invention can be used as probes to detect, characterize, and quantify LSNA in, and isolate LSNA from, transcript-derived nucleic acid samples. In one aspect, the isolated nucleic acid molecules of the present invention can be used as hybridization probes to detect, characterize by length, and quantify mRNA by Northern blot of total or poly-A⁺-selected RNA samples. In another aspect, the isolated nucleic acid molecules of the present invention can be used as hybridization probes to detect, characterize by location, and quantify mRNA by in situ hybridization to tissue sections. See, e.g., Schwarchzacher et al, In Situ Hybridization, Springer-Verlag New York (2000), the disclosure of which is incorporated herein by reference in its entirety. In another preferred embodiment, the isolated nucleic acid molecules of the present invention can be used as hybridization probes to measure the representation of clones in a cDNA library or to isolate hybridizing nucleic acid molecules acids from cDNA libraries, permitting sequence level characterization of mRNAs that hybridize to LSNAs, including, without limitations, identification of deletions, insertions, substitutions, truncations, alternatively spliced forms and single nucleotide polymorphisms. In yet another preferred embodiment, the nucleic acid molecules of the instant invention may be used in microarrays.

[0148] All of the aforementioned probe techniques are well within the skill in the art, and are described at greater length in standard texts such as Sambrook (2001), supra; Ausubel (1999), supra; and Walker et al. (eds.), The Nucleic Acids Protocols Handbook, Humana Press (2000), the disclosures of which are incorporated herein by reference in their entirety.

[0149] Thus, in one embodiment, a nucleic acid molecule of the invention may be used as a probe or primer to identify or amplify a second nucleic acid molecule that selectively hybridizes to the nucleic acid molecule of the invention. In a preferred embodiment, the probe or primer is derived from a nucleic acid molecule encoding an LSP. In a more preferred embodiment, the probe or primer is derived from a nucleic acid molecule encoding a polypeptide having an amino acid sequence of SEQ ID NO: 165 through 284. In another preferred embodiment, the probe or primer is derived from an LSNA. In a more preferred embodiment, the probe or primer is derived from a nucleic acid molecule having a nucleotide sequence of SEQ ID NO: 1 through 164.

[0150] In general, a probe or primer is at least 10 nucleotides in length, more preferably at least 12, more preferably at least 14 and even more preferably at least 16 or 17 nucleotides in length. In an even more preferred embodiment, the probe or primer is at least 18 nucleotides in length, even more preferably at least 20 nucleotides and even more preferably at least 22 nucleotides in length. Primers and probes may also be longer in length. For instance, a probe or primer may be 25 nucleotides in length, or may be 30, 40 or 50 nucleotides in length. Methods of performing nucleic acid hybridization using oligonucleotide probes are well-known in the art. See, e.g., Sambrook et al., 1989, supra, Chapter 11 and pp. 11.31-11.32 and 11.40-11.44, which describes radiolabeling of short probes, and pp. 11.45-11.53, which describe hybridization conditions for oligonucleotide probes, including specific conditions for probe hybridization (pp. 11.50-11.51).

[0151] Methods of performing primer-directed amplification are also well-known in the art. Methods for performing the polymerase chain reaction (PCR) are compiled, inter alia, in McPherson, PCR Basics: From Background to Bench, Springer Verlag (2000); Innis et al. (eds.), PCR Applications: Protocols for Functional Genomics, Academic Press (1999); Gelfand et al. (eds.), PCR Strategies, Academic Press (1998); Newton et al., PCR, Springer-Verlag New York (1997); Burke (ed.), PCR: Essential Techniques, John Wiley & Son Ltd (1996); White (ed.), PCR Cloning Protocols: From Molecular Cloning to Genetic Engineering, Vol. 67, Humana Press (1996); McPherson et al. (eds.), PCR 2: A Practical Approach, Oxford University Press, Inc. (1995); the disclosures of which are incorporated herein by reference in their entireties. Methods for performing RT-PCR are collected, e.g., in Siebert et al (eds.), Gene Cloning and Analysis by RT-PCR, Eaton Publishing Company/Bio Techniques Books Division, 1998; Siebert (ed.), PCR Technique:RT-PCR, Eaton Publishing Company/BioTechniques Books (1995); the disclosure of which is incorporated herein by reference in its entirety.

[0152] PCR and hybridization methods may be used to identify and/or isolate allelic variants, homologous nucleic acid molecules and fragments of the nucleic acid molecules of the invention. PCR and hybridization methods may also be used to identify, amplify and/or isolate nucleic acid molecules that encode homologous proteins, analogs, fusion protein or muteins of the invention. The nucleic acid primers of the present invention can be used to prime amplification of nucleic acid molecules of the invention, using transcript-derived or genomic DNA as template.

[0153] The nucleic acid primers of the present invention can also be used, for example, to prime single base extension (SBE) for SNP detection (See, e.g., U.S. Pat. No. 6,004,744. the disclosure of which is incorporated herein by reference in its entirety).

[0154] Isothermal amplification approaches, such as rolling circle amplification, are also now well-described. See, e.g., Schweitzer et a., Curr. Opin. Biotechnol. 12(1): 21-7 (2001); U.S. Pat. Nos. 5,854,033 and 5,714,320; and international patent publications WO 97/19193 and WO 00/15779, the disclosures of which are incorporated herein by reference in their entireties. Rolling circle amplification can be combined with other techniques to facilitate SNP detection. See, e.g., Lizardi et al., Nature Genet. 19(3): 225-32 (1998).

[0155] Nucleic acid molecules of the present invention may be bound to a substrate either covalently or noncovalently. The substrate can be porous or solid, planar or non-planar, unitary or distributed. The bound nucleic acid molecules may be used as hybridization probes, and may be labeled or unlabeled. In a preferred embodiment, the bound nucleic acid molecules are unlabeled.

[0156] In one embodiment. the nucleic acid molecule of the present invention is bound to a porous substrate, e.g., a membrane, typically comprising nitrocellulose, nylon, or positively-charged derivatized nylon. The nucleic acid molecule of the present invention can be used to detect a hybridizing nucleic acid molecule that is present within a labeled nucleic acid sample, e.g., a sample of transcript-derived nucleic acids. In another embodiment, the nucleic acid molecule is bound to a solid substrate, including, without limitation, glass, amorphous silicon, crystalline silicon or plastics. Examples of plastics include, without limitation, polymethylacrylic, polyethylene, polypropylene, polyacrylate, polymethylmethacrylate, polyvinylchloride, polytetrafluoroethylene, polystyrene, polycarbonate, polyacetal, polysulfone, celluloseacetate, cellulosenitrate, nitrocellulose, or mixtures thereof. The solid substrate may be any shape, including rectangular, disk-like and spherical. In a preferred embodiment, the solid substrate is a microscope slide or slide-shaped substrate.

[0157] The nucleic acid molecule of the present invention can be attached covalently to a surface of the support substrate or applied to a derivatized surface in a chaotropic agent that facilitates denaturation and adherence by presumed noncovalent interactions, or some combination thereof. The nucleic acid molecule of the present invention can be bound to a substrate to which a plurality of other nucleic acids are concurrently bound, hybridization to each of the plurality of bound nucleic acids being separately detectable. At low density, e.g. on a porous membrane, these substrate-bound collections are typically denominated macroarrays; at higher density, typically on a solid support, such as glass, these substrate bound collections of plural nucleic acids are colloquially termed microarrays. As used herein, the term microarray includes arrays of all densities. It is, therefore, another aspect of the invention to provide microarrays that include the nucleic acids of the present invention.

[0158] Expression Vectors, Host Cells and Recombinant Methods of Producing Polypeptides

[0159] Another aspect of the present invention relates to vectors that comprise one or more of the isolated nucleic acid molecules of the present invention, and host cells in which such vectors have been introduced.

[0160] The vectors can be used, inter alia, for propagating the nucleic acids of the present invention in host cells (cloning vectors), for shuttling the nucleic acids of the present invention between host cells derived from disparate organisms (shuttle vectors), for inserting the nucleic acids of the present invention into host cell chromosomes (insertion vectors), for expressing sense or antisense RNA transcripts of the nucleic acids of the present invention in vitro or within a host cell, and for expressing polypeptides encoded by the nucleic acids of the present invention, alone or as fusions to heterologous polypeptides (expression vectors). Vectors of the present invention will often be suitable for several such uses.

[0161] Vectors are by now well-known in the art, and are described, inter alia, in Jones et al. (eds.), Vectors: Cloning Applications: Essential Techniques (Essential Techniques Series), John Wiley & Son Ltd. (1998); Jones et al. (eds.), Vectors: Expression Systems: Essential Techniques (Essential Techniques Series), John Wiley & Son Ltd. (1998); Gacesa et al., Vectors: Essential Data, John Wiley & Sons Ltd. (1995); Cid-Arregui (eds.), Viral Vectors: Basic Science and Gene Therapy, Eaton Publishing Co. (2000); Sambrook (2001), supra; Ausubel (1999), supra; the disclosures of which are incorporated herein by reference in their entireties. Furthermore, an enormous variety of vectors are available commercially. Use of existing vectors and modifications thereof being well within the skill in the art, only basic features need be described here.

[0162] Nucleic acid sequences may be expressed by operatively linking them to an expression control sequence in an appropriate expression vector and employing that expression vector to transform an appropriate unicellular host. Expression control sequences are sequences which control the transcription, post-transcriptional events and translation of nucleic acid sequences. Such operative linking of a nucleic sequence of this invention to an expression control sequence, of course, includes, if not already part of the nucleic acid sequence, the provision of a translation initiation codon, ATG or GTG, in the correct reading frame upstream of the nucleic acid sequence.

[0163] A wide variety of host/expression vector combinations may be employed in expressing the nucleic acid sequences of this invention. Useful expression vectors, for example, may consist of segments of chromosomal, non-chromosomal and synthetic nucleic acid sequences.

[0164] In one embodiment, prokaryotic cells may be used with an appropriate vector. Prokaryotic host cells are often used for cloning and expression. In a preferred embodiment, prokaryotic host cells include E. coli, Pseudomonas, Bacillus and Streptomyces. In a preferred embodiment, bacterial host cells are used to express the nucleic acid molecules of the instant invention. Useful expression vectors for bacterial hosts include bacterial plasmids, such as those from E. coli, Bacillus or Streptomyces, including pBluescript, pGEX-2T, pUC vectors, col E1, pCR1, pBR322, pMB9 and their derivatives, wider host range plasmids, such as RP4, phage DNAs, e.g., the numerous derivatives of phage lambda, e.g., NM989, λGT10 and λGT11, and other phages, e.g., M13 and filamentous single-stranded phage DNA. Where E. coli is used as host, selectable markers are, analogously, chosen for selectivity in gram negative bacteria: e.g., typical markers confer resistance to antibiotics, such as ampicillin, tetracycline, chloramphenicol, kanamycin, streptomycin and zeocin; auxotrophic markers can also be used.

[0165] In other embodiments, eukaryotic host cells, such as yeast, insect, mammalian or plant cells, may be used. Yeast cells, typically S. cerevisiae, are useful for eukaryotic genetic studies, due to the ease of targeting genetic changes by homologous recombination and the ability to easily complement genetic defects using recombinantly expressed proteins. Yeast cells are useful for identifying interacting protein components, e.g. through use of a two-hybrid system. In a preferred embodiment, yeast cells are useful for protein expression. Vectors of the present invention for use in yeast will typically, but not invariably, contain an origin of replication suitable for use in yeast and a selectable marker that is functional in yeast. Yeast vectors include Yeast Integrating plasmids (e.g., YIp5) and Yeast Replicating plasmids (the YRp and YEp series plasmids), Yeast Centromere plasmids (the YCp series plasmids), Yeast Artificial Chromosomes (YACs) which are based on yeast linear plasmids, denoted YLp, pGPD-2, 2μ plasmids and derivatives thereof, and improved shuttle vectors such as those described in Gietz et al., Gene, 74: 527-34 (1988) (YIplac, YEplac and YCplac). Selectable markers in yeast vectors include a variety of auxotrophic markers, the most common of which are (in Saccharomyces cerevisiae) URA3, HIS3, LEU2, TRP1 and LYS2, which complement specific auxotrophic mutations, such as ura3-52, his3-D1, leu2-D1, trp1-D1 and lys2-201.

[0166] Insect cells are often chosen for high efficiency protein expression. Where the host cells are from Spodoptera frugiperda, e.g., Sf9 and Sf21 cell lines, and expresSF™ cells (Protein Sciences Corp., Meriden, Conn., USA)), the vector replicative strategy is typically based upon the baculovirus life cycle. Typically, baculovirus transfer vectors are used to replace the wild-type AcMNPV polyhedrin gene with a heterologous gene of interest. Sequences that flank the polyhedrin gene in the wild-type genome are positioned 5′ and 3′ of the expression cassette on the transfer vectors. Following co-transfection with AcMNPV DNA, a homologous recombination event occurs between these sequences resulting in a recombinant virus carrying the gene of interest and the polyhedrin or p10 promoter. Selection can be based upon visual screening for lacZ fusion activity.

[0167] In another embodiment, the host cells may be mammalian cells, which are particularly useful for expression of proteins intended as pharmaceutical agents, and for screening of potential agonists and antagonists of a protein or a physiological pathway. Mammalian vectors intended for autonomous extrachromosomal replication will typically include a viral origin, such as the SV40 origin (for replication in cell lines expressing the large T-antigen, such as COS1 and COS7 cells), the papillomavirus origin, or the EBV origin for long term episomal replication (for use, e.g., in 293-EBNA cells, which constitutively express the EBV EBNA-1 gene product and adenovirus E1A). Vectors intended for integration, and thus replication as part of the mammalian chromosome, can, but need not, include an origin of replication functional in mammalian cells, such as the SV40 origin. Vectors based upon viruses, such as adenovirus, adeno-associated virus, vaccinia virus, and various mammalian retroviruses, will typically replicate according to the viral replicative strategy. Selectable markers for use in mammalian cells include resistance to neomycin (G418), blasticidin, hygromycin and to zeocin, and selection based upon the purine salvage pathway using HAT medium.

[0168] Expression in mammalian cells can be achieved using a variety of plasmids, including pSV2, pBC12BI, and p91023, as well as lytic virus vectors (e.g., vaccinia virus, adeno virus, and baculovirus), episomal virus vectors (e.g., bovine papillomavirus), and retroviral vectors (e.g., murine retroviruses). Useful vectors for insect cells include baculoviral vectors and pVL 941.

[0169] Plant cells can also be used for expression, with the vector replicon typically derived from a plant virus (e.g., cauliflower mosaic virus, CaMV; tobacco mosaic virus, TMV) and selectable markers chosen for suitability in plants.

[0170] It is known that codon usage of different host cells may be different. For example, a plant cell and a human cell may exhibit a difference in codon preference for encoding a particular amino acid. As a result, human mRNA may not be efficiently translated in a plant, bacteria or insect host cell. Therefore, another embodiment of this invention is directed to codon optimization. The codons of the nucleic acid molecules of the invention may be modified to resemble, as much as possible, genes naturally contained within the host cell without altering the amino acid sequence encoded by the nucleic acid molecule.

[0171] Any of a wide variety of expression control sequences may be used in these vectors to express the DNA sequences of this invention. Such useful expression control sequences include the expression control sequences associated with structural genes of the foregoing expression vectors. Expression control sequences that control transcription include, e.g., promoters, enhancers and transcription termination sites. Expression control sequences in eukaryotic cells that control post-transcriptional events include splice donor and acceptor sites and sequences that modify the half-life of the transcribed RNA, e.g., sequences that direct poly(A) addition or binding sites for RNA-binding proteins. Expression control sequences that control translation include ribosome binding sites, sequences which direct targeted expression of the polypeptide to or within particular cellular compartments, and sequences in the 5′ and 3′ untranslated regions that modify the rate or efficiency of translation.

[0172] Examples of useful expression control sequences for a prokaryote, e.g., E. coli, will include a promoter, often a phage promoter, such as phage lambda pL promoter, the trc promoter, a hybrid derived from the trp and lac promoters, the bacteriophage T7 promoter (in E. coli cells engineered to express the T7 polymerase), the TAC or TRC system, the major operator and promoter regions of phage lambda, the control regions of fd coat protein, or the araBAD operon. Prokaryotic expression vectors may further include transcription terminators, such as the aspA terminator, and elements that facilitate translation, such as a consensus ribosome binding site and translation termination codon, Schomer et al., Proc. Natl. Acad. Sci. USA 83: 8506-8510 (1986).

[0173] Expression control sequences for yeast cells, typically S. cerevisiae, will include a yeast promoter, such as the CYCI promoter, the GAL1 promoter, the GAL10 promoter, ADH1 promoter, the promoters of the yeast_-mating system, or the GPD promoter, and will typically have elements that facilitate transcription termination, such as the transcription termination signals from the CYC1 or ADH1 gene.

[0174] Expression vectors useful for expressing proteins in mammalian cells will include a promoter active in mammalian cells. These promoters include those derived from mammalian viruses, such as the enhancer-promoter sequences from the immediate early gene of the human cytomegalovirus (CMV), the enhancer-promoter sequences from the Rous sarcoma virus long terminal repeat (RSV LTR), the enhancer-promoter from SV40 or the early and late promoters of adenovirus. Other expression control sequences include the promoter for 3-phosphoglycerate kinase or other glycolytic enzymes, the promoters of acid phosphatase. Other expression control sequences include those from the gene comprising the LSNA of interest. Often, expression is enhanced by incorporation of polyadenylation sites, such as the late SV40 polyadenylation site and the polyadenylation signal and transcription termination sequences from the bovine growth hormone (BGH) gene, and ribosome binding sites. Furthermore, vectors can include introns, such as intron II of rabbit β-globin gene and the SV40 splice elements.

[0175] Preferred nucleic acid vectors also include a selectable or amplifiable marker gene and means for amplifying the copy number of the gene of interest. Such marker genes are well-known in the art. Nucleic acid vectors may also comprise stabilizing sequences (e.g., ori- or ARS-like sequences and telomere-like sequences), or may alternatively be designed to favor directed or non-directed integration into the host cell genome. In a preferred embodiment, nucleic acid sequences of this invention are inserted in frame into an expression vector that allows high level expression of an RNA which encodes a protein comprising the encoded nucleic acid sequence of interest. Nucleic acid cloning and sequencing methods are well-known to those of skill in the art and are described in an assortment of laboratory manuals, including Sambrook (1989), supra, Sambrook (2000), supra; and Ausubel (1992), supra, Ausubel (1999), supra. Product information from manufacturers of biological, chemical and immunological reagents also provide useful information.

[0176] Expression vectors may be either constitutive or inducible. Inducible vectors include either naturally inducible promoters, such as the trc promoter, which is regulated by the lac operon, and the pL promoter, which is regulated by tryptophan, the MMTV-LTR promoter, which is inducible by dexamethasone, or can contain synthetic promoters and/or additional elements that confer inducible control on adjacent promoters. Examples of inducible synthetic promoters are the hybrid Plac/ara-1 promoter and the PLtetO-1 promoter. The PltetO-1 promoter takes advantage of the high expression levels from the PL promoter of phage lambda, but replaces the lambda repressor sites with two copies of operator 2 of the Tn10 tetracycline resistance operon, causing this promoter to be tightly repressed by the Tet repressor protein and induced in response to tetracycline (Tc) and Tc derivatives such as anhydrotetracycline. Vectors may also be inducible because they contain hormone response elements, such as the glucocorticoid response element (GRE) and the estrogen response element (ERE), which can confer hormone inducibility where vectors are used for expression in cells having the respective hormone receptors. To reduce background levels of expression, elements responsive to ecdysone, an insect hormone, can be used instead, with coexpression of the ecdysone receptor.

[0177] In one aspect of the invention, expression vectors can be designed to fuse the expressed polypeptide to small protein tags that facilitate purification and/or visualization. Tags that facilitate purification include a polyhistidine tag that facilitates purification of the fusion protein by immobilized metal affinity chromatography, for example using NiNTA resin (Qiagen Inc., Valencia, Calif., USA) or TALON™ resin (cobalt immobilized affinity chromatography medium, Clontech Labs, Palo Alto, Calif., USA). The fusion protein can include a chitin-binding tag and self-excising intein, permitting chitin-based purification with self-removal of the fused tag (IMPACT™ system, New England Biolabs, Inc., Beverley, Mass., USA). Alternatively, the fusion protein can include a calmodulin-binding peptide tag, permitting purification by calmodulin affinity resin (Stratagene, La Jolla, Calif., USA), or a specifically excisable fragment of the biotin carboxylase carrier protein, permitting purification of in vivo biotinylated protein using an avidin resin and subsequent tag removal (Promega, Madison, Wis., USA). As another useful alternative, the proteins of the present invention can be expressed as a fusion protein with glutathione-S-transferase, the affinity and specificity of binding to glutathione permitting purification using glutathione affinity resins, such as Glutathione-Superflow Resin (Clontech Laboratories, Palo Alto, Calif., USA), with subsequent elution with free glutathione. Other tags include, for example, the Xpress epitope, detectable by anti-Xpress antibody (Invitrogen, Carlsbad, Calif., USA), a myc tag, detectable by anti-myc tag antibody, the V5 epitope, detectable by anti-V5 antibody (Invitrogen, Carlsbad, Calif., USA), FLAG® epitope, detectable by anti-FLAG® antibody (Stratagene, La Jolla, Calif., USA), and the HA epitope.

[0178] For secretion of expressed proteins, vectors can include appropriate sequences that encode secretion signals, such as leader peptides. For example, the pSecTag2 vectors (Invitrogen, Carlsbad, Calif., USA) are 5.2 kb mammalian expression vectors that carry the secretion signal from the V-J2-C region of the mouse Ig kappa-chain for efficient secretion of recombinant proteins from a variety of mammalian cell lines.

[0179] Expression vectors can also be designed to fuse proteins encoded by the heterologous nucleic acid insert to polypeptides that are larger than purification and/or identification tags. Useful fusion proteins include those that permit display of the encoded protein on the surface of a phage or cell, fusion to intrinsically fluorescent proteins, such as those that have a green fluorescent protein (GFP)-like chromophore, fusions to the IgG Fc region, and fusion proteins for use in two hybrid systems.

[0180] Vectors for phage display fuse the encoded polypeptide to, e.g., the gene III protein (PIII) or gene VIII protein (PVIII) for display on the surface of filamentous phage, such as M13. See Barbas et al., Phage Display: A Laboratory Manual, Cold Spring Harbor Laboratory Press (2001); Kay et al. (eds.), Phage Display of Peptides and Proteins: A Laboratory Manual, Academic Press, Inc., (1996); Abelson et al. (eds.), Combinatorial Chemistry (Methods in Enzymology, Vol. 267) Academic Press (1996). Vectors for yeast display, e.g. the pYD1 yeast display vector (Invitrogen, Carlsbad, Calif., USA), use the -agglutinin yeast adhesion receptor to display recombinant protein on the surface of S. cerevisiae. Vectors for mammalian display, e.g., the pDisplay™ vector (Invitrogen, Carlsbad, Calif., USA), target recombinant proteins using an N-terminal cell surface targeting signal and a C-terminal transmembrane anchoring domain of platelet derived growth factor receptor.

[0181] A wide variety of vectors now exist that fuse proteins encoded by heterologous nucleic acids to the chromophore of the substrate-independent, intrinsically fluorescent green fluorescent protein from Aequorea victoria (“GFP”) and its variants. The GFP-like chromophore can be selected from GFP-like chromophores found in naturally occurring proteins, such as A. victoria GFP (GenBank accession number AAA27721), Renilla reniformis GFP, FP583 (GenBank accession no. AF168419) (DsRed), FP593 (AF272711), FP483 (AF168420), FP484 (AF168424), FP595 (AF246709), FP486 (AF168421), FP538 (AF168423), and FP506 (AF168422), and need include only so much of the native protein as is needed to retain the chromophore's intrinsic fluorescence. Methods for determining the minimal domain required for fluorescence are known in the art. See Li et al., J. Biol. Chem. 272: 28545-28549 (1997). Alternatively, the GFP-like chromophore can be selected from GFP-like chromophores modified from those found in nature. The methods for engineering such modified GFP-like chromophores and testing them for fluorescence activity, both alone and as part of protein fusions, are well-known in the art. See Heim et al., Curr. Biol. 6: 178-182 (1996) and Palm et al., Methods Enzymol. 302: 378-394 (1999), incorporated herein by reference in its entirety. A variety of such modified chromophores are now commercially available and can readily be used in the fusion proteins of the present invention. These include EGFP (“enhanced GFP”), EBFP (“enhanced blue fluorescent protein”), BFP2, EYFP (“enhanced yellow fluorescent protein”), ECFP (“enhanced cyan fluorescent protein”) or Citrine. EGFP (see, e.g, Cormack et al., Gene 173: 33-38 (1996); U.S. Pat. Nos. 6,090,919 and 5,804,387) is found on a variety of vectors, both plasmid and viral, which are available commercially (Clontech Labs, Palo Alto, Calif., USA); EBFP is optimized for expression in mammalian cells whereas BFP2, which retains the original jellyfish codons, can be expressed in bacteria (see, e.g,. Heim et al., Curr. Biol. 6: 178-182 (1996) and Cormack et aL, Gene 173: 33-38 (1996)). Vectors containing these blue-shifted variants are available from Clontech Labs (Palo Alto, Calif., USA). Vectors containing EYFP, ECFP (see, e.g., Heim et al., Curr. Biol. 6: 178-182 (1996); Miyawaki et al., Nature 388: 882-887 (1997)) and Citrine (see, e.g., Heikal et al., Proc. Natl. Acad. Sci. USA 97: 11996-12001 (2000)) are also available from Clontech Labs. The GFP-like chromophore can also be drawn from other modified GFPs, including those described in U.S. Pat. Nos. 6,124,128; 6,096,865; 6,090,919; 6,066,476; 6,054,321; 6,027,881; 5,968,750; 5,874,304; 5,804,387; 5,777,079; 5,741,668; and 5,625,048, the disclosures of which are incorporated herein by reference in their entireties. See also Conn (ed.), Green Fluorescent Protein (Methods in Enzymology, Vol. 302), Academic Press, Inc. (1999). The GFP-like chromophore of each of these GFP variants can usefully be included in the fusion proteins of the present invention.

[0182] Fusions to the IgG Fc region increase serum half life of protein pharmaceutical products through interaction with the FcRn receptor (also denominated the FcRp receptor and the Brambell receptor, FcRb), further described in International Patent Application Nos. WO 97/43316, WO 97/34631, WO 96/32478, WO 96/18412.

[0183] For long-term, high-yield recombinant production of the proteins, protein fusions, and protein fragments of the present invention, stable expression is preferred. Stable expression is readily achieved by integration into the host cell genome of vectors having selectable markers, followed by selection of these integrants. Vectors such as pUB6/V5-His A, B, and C (Invitrogen, Carlsbad, Calif., USA) are designed for high-level stable expression of heterologous proteins in a wide range of mammalian tissue types and cell lines. pUB6/V5-His uses the promoter/enhancer sequence from the human ubiquitin C gene to drive expression of recombinant proteins: expression levels in 293, CHO, and NIH3T3 cells are comparable to levels from the CMV and human EF-la promoters. The bsd gene permits rapid selection of stably transfected mammalian cells with the potent antibiotic blasticidin.

[0184] Replication incompetent retroviral vectors, typically derived from Moloney murine leukemia virus, also are useful for creating stable transfectants having integrated provirus. The highly efficient transduction machinery of retroviruses, coupled with the availability of a variety of packaging cell lines such as RetroPack™ PT 67, EcoPac2™-293, AmphoPack-293, and GP2-293 cell lines (all available from Clontech Laboratories, Palo Alto, Calif., USA), allow a wide host range to be infected with high efficiency; varying the multiplicity of infection readily adjusts the copy number of the integrated provirus.

[0185] Of course, not all vectors and expression control sequences will function equally well to express the nucleic acid sequences of this invention. Neither will all hosts function equally well with the same expression system. However, one of skill in the art may make a selection among these vectors, expression control sequences and hosts without undue experimentation and without departing from the scope of this invention. For example, in selecting a vector, the host must be considered because the vector must be replicated in it. The vector's copy number, the ability to control that copy number, the ability to control integration, if any, and the expression of any other proteins encoded by the vector, such as antibiotic or other selection markers, should also be considered. The present invention further includes host cells comprising the vectors of the present invention, either present episomally within the cell or integrated, in whole or in part, into the host cell chromosome. Among other considerations, some of which are described above, a host cell strain may be chosen for its ability to process the expressed protein in the desired fashion. Such post-translational modifications of the polypeptide include, but are not limited to, acetylation, carboxylation, glycosylation, phosphorylation, lipidation, and acylation, and it is an aspect of the present invention to provide LSPs with such post-translational modifications.

[0186] Polypeptides of the invention may be post-translationally modified. Post-translational modifications include phosphorylation of amino acid residues serine, threonine and/or tyrosine, N-linked and/or O-linked glycosylation, methylation, acetylation, prenylation, methylation, acetylation, arginylation, ubiquination and racemization. One may determine whether a polypeptide of the invention is likely to be post-translationally modified by analyzing the sequence of the polypeptide to determine if there are peptide motifs indicative of sites for post-translational modification. There are a number of computer programs that permit prediction of post-translational modifications. See, e.g., www.expasy.org (accessed Aug. 31, 2001), which includes PSORT, for prediction of protein sorting signals and localization sites, SignalP, for prediction of signal peptide cleavage sites, MITOPROT and Predotar, for prediction of mitochondrial targeting sequences, NetOGlyc, for prediction of type O-glycosylation sites in mammalian proteins, big-PI Predictor and DGPI, for prediction of prenylation-anchor and cleavage sites, and NetPhos, for prediction of Ser, Thr and Tyr phosphorylation sites in eukaryotic proteins. Other computer programs, such as those included in GCG, also may be used to determine post-translational modification peptide motifs.

[0187] General examples of types of post-translational modifications may be found in web sites such as the Delta Mass database http://www.abrf.org/ABRF/Research Committees/deltamass/deltamass.html (accessed Oct. 19, 2001); “GlycoSuiteDB: a new curated relational database of glycoprotein glycan structures and their biological sources” Cooper et al. Nucleic Acids Res. 29; 332-335 (2001) and http://www.glycosuite.com/ (accessed Oct. 19, 2001); “O-GLYCBASE version 4.0: a revised database of O-glycosylated proteins” Gupta et al. Nucleic Acids Research, 27: 370-372 (1999) and http://www.cbs.dtu.dk/databases/OGLYCBASE/ (accessed Oct. 19, 2001); “PhosphoBase, a database of phosphorylation sites: release 2.0.”, Kreegipuu et al. Nucleic Acids Res 27(l):237-239 (1999) and http://www.cbs.dtu.dk/databases/PhosphoBase/ (accessed Oct. 19, 2001); or http://pir.georgetown.edu/pirwww/search/textresid.html (accessed Oct. 19, 2001).

[0188] Tumorigenesis is often accompanied by alterations in the post-translational modifications of proteins. Thus, in another embodiment, the invention provides polypeptides from cancerous cells or tissues that have altered post-translational modifications compared to the post-translational modifications of polypeptides from normal cells or tissues. A number of altered post-translational modifications are known. One common alteration is a change in phosphorylation state, wherein the polypeptide from the cancerous cell or tissue is hyperphosphorylated or hypophosphorylated compared to the polypeptide from a normal tissue, or wherein the polypeptide is phosphorylated on different residues than the polypeptide from a normal cell. Another common alteration is a change in glycosylation state, wherein the polypeptide from the cancerous cell or tissue has more or less glycosylation than the polypeptide from a normal tissue, and/or wherein the polypeptide from the cancerous cell or tissue has a different type of glycosylation than the polypeptide from a noncancerous cell or tissue. Changes in glycosylation may be critical because carbohydrate-protein and carbohydrate-carbohydrate interactions are important in cancer cell progression, dissemination and invasion. See, e.g., Barchi, Curr. Pharm. Des. 6: 485-501 (2000), Verma, Cancer Biochem. Biophys. 14: 151-162 (1994) and Dennis et al., Bioessays 5: 412-421 (1999).

[0189] Another post-translational modification that may be altered in cancer cells is prenylation. Prenylation is the covalent attachment of a hydrophobic prenyl group (either famesyl or geranylgeranyl) to a polypeptide. Prenylation is required for localizing a protein to a cell membrane and is often required for polypeptide function. For instance, the Ras superfamily of GTPase signaling proteins must be prenylated for function in a cell. See, e.g., Prendergast et al., Semin. Cancer Biol. 10: 443-452 (2000) and Khwaja et al., Lancet 355: 741-744 (2000).

[0190] Other post-translation modifications that may be altered in cancer cells include, without limitation, polypeptide methylation, acetylation, arginylation or racemization of amino acid residues. In these cases, the polypeptide from the cancerous cell may exhibit either increased or decreased amounts of the post-translational modification compared to the corresponding polypeptides from noncancerous cells.

[0191] Other polypeptide alterations in cancer cells include abnormal polypeptide cleavage of proteins and aberrant protein-protein interactions. Abnormal polypeptide cleavage may be cleavage of a polypeptide in a cancerous cell that does not usually occur in a normal cell, or a lack of cleavage in a cancerous cell, wherein the polypeptide is cleaved in a normal cell. Aberrant protein-protein interactions may be either covalent cross-linking or non-covalent binding between proteins that do not normally bind to each other. Alternatively, in a cancerous cell, a protein may fail to bind to another protein to which it is bound in a noncancerous cell. Alterations in cleavage or in protein-protein interactions may be due to over- or underproduction of a polypeptide in a cancerous cell compared to that in a normal cell, or may be due to alterations in post-translational modifications (see above) of one or more proteins in the cancerous cell. See, e.g., Henschen-Edman, Ann. N.Y. Acad. Sci. 936: 580-593 (2001).

[0192] Alterations in polypeptide post-translational modifications, as well as changes in polypeptide cleavage and protein-protein interactions, may be determined by any method known in the art. For instance, alterations in phosphorylation may be determined by using anti-phosphoserine, anti-phosphothreonine or anti-phosphotyrosine antibodies or by amino acid analysis. Glycosylation alterations may be determined using antibodies specific for different sugar residues, by carbohydrate sequencing, or by alterations in the size of the glycoprotein, which can be determined by, e.g., SDS polyacrylamide gel electrophoresis (PAGE). Other alterations of post-translational modifications, such as prenylation, racemization, methylation, acetylation and arginylation, may be determined by chemical analysis, protein sequencing, amino acid analysis, or by using antibodies specific for the particular post-translational modifications. Changes in protein-protein interactions and in polypeptide cleavage may be analyzed by any method known in the art including, without limitation, non-denaturing PAGE (for non-covalent protein-protein interactions), SDS PAGE (for covalent protein-protein interactions and protein cleavage), chemical cleavage, protein sequencing or immunoassays.

[0193] In another embodiment, the invention provides polypeptides that have been post-translationally modified. In one embodiment, polypeptides may be modified enzymatically or chemically, by addition or removal of a post-translational modification. For example, a polypeptide may be glycosylated or deglycosylated enzymatically. Similarly, polypeptides may be phosphorylated using a purified kinase, such as a MAP kinase (e.g, p38, ERK, or JNK) or a tyrosine kinase (e.g., Src or erbB2). A polypeptide may also be modified through synthetic chemistry. Alternatively, one may isolate the polypeptide of interest from a cell or tissue that expresses the polypeptide with the desired post-translational modification. In another embodiment, a nucleic acid molecule encoding the polypeptide of interest is introduced into a host cell that is capable of post-translationally modifying the encoded polypeptide in the desired fashion. If the polypeptide does not contain a motif for a desired post-translational modification, one may alter the post-translational modification by mutating the nucleic acid sequence of a nucleic acid molecule encoding the polypeptide so that it contains a site for the desired post-translational modification. Amino acid sequences that may be post-translationally modified are known in the art. See, e.g., the programs described above on the website www.expasy.org. The nucleic acid molecule is then be introduced into a host cell that is capable of post-translationally modifying the encoded polypeptide. Similarly, one may delete sites that are post-translationally modified by either mutating the nucleic acid sequence so that the encoded polypeptide does not contain the post-translational modification motif, or by introducing the native nucleic acid molecule into a host cell that is not capable of post-translationally modifying the encoded polypeptide.

[0194] In selecting an expression control sequence, a variety of factors should also be considered. These include, for example, the relative strength of the sequence, its controllability, and its compatibility with the nucleic acid sequence of this invention, particularly with regard to potential secondary structures. Unicellular hosts should be selected by consideration of their compatibility with the chosen vector, the toxicity of the product coded for by the nucleic acid sequences of this invention, their secretion characteristics, their ability to fold the polypeptide correctly, their fermentation or culture requirements, and the ease of purification from them of the products coded for by the nucleic acid sequences of this invention.

[0195] The recombinant nucleic acid molecules and more particularly, the expression vectors of this invention may be used to express the polypeptides of this invention as recombinant polypeptides in a heterologous host cell. The polypeptides of this invention may be full-length or less than full-length polypeptide fragments recombinantly expressed from the nucleic acid sequences according to this invention. Such polypeptides include analogs, derivatives and muteins that may or may not have biological activity.

[0196] Vectors of the present invention will also often include elements that permit in vitro transcription of RNA from the inserted heterologous nucleic acid. Such vectors typically include a phage promoter, such as that from T7, T3, or SP6, flanking the nucleic acid insert. Often two different such promoters flank the inserted nucleic acid, permitting separate in vitro production of both sense and antisense strands.

[0197] Transformation and other methods of introducing nucleic acids into a host cell (e.g., conjugation, protoplast transformation or fusion, transfection, electroporation, liposome delivery, membrane fusion techniques, high velocity DNA-coated pellets, viral infection and protoplast fusion) can be accomplished by a variety of methods which are well-known in the art (See, for instance, Ausubel, supra, and Sambrook et al., supra). Bacterial, yeast, plant or mammalian cells are transformed or transfected with an expression vector, such as a plasmid, a cosmid, or the like, wherein the expression vector comprises the nucleic acid of interest. Alternatively, the cells may be infected by a viral expression vector comprising the nucleic acid of interest. Depending upon the host cell, vector, and method of transformation used, transient or stable expression of the polypeptide will be constitutive or inducible. One having ordinary skill in the art will be able to decide whether to express a polypeptide transiently or stably, and whether to express the protein constitutively or inducibly.

[0198] A wide variety of unicellular host cells are useful in expressing the DNA sequences of this invention. These hosts may include well-known eukaryotic and prokaryotic hosts, such as strains of, fungi, yeast, insect cells such as Spodoptera frugiperda (SF9), animal cells such as CHO, as well as plant cells in tissue culture. Representative examples of appropriate host cells include, but are not limited to, bacterial cells, such as E. coli, Caulobacter crescentus, Streptomyces species, and Salmonella typhimurium; yeast cells, such as Saccharomyces cerevisiae, Schizosaccharomyces pombe, Pichia pastoris, Pichia methanolica; insect cell lines, such as those from Spodoptera frugiperdal, e.g., Sf9 and Sf21 cell lines, and expresSF™ cells (Protein Sciences Corp., Meriden, Conn., USA), Drosophila S2 cells, and Trichoplusia ni High Five® Cells (Invitrogen, Carlsbad, Calif., USA); and mammalian cells. Typical mammalian cells include BHK cells, BSC 1 cells, BSC 40 cells, BMT 10 cells, VERO cells, COS1 cells, COS7 cells, Chinese hamster ovary (CHO) cells, 3T3 cells, NIH 3T3 cells, 293 cells, HEPG2 cells, HeLa cells, L cells, MDCK cells, HEK293 cells, W138 cells, murine ES cell lines (e.g., from strains 129/SV, C57/BL6, DBA-1, 129/SVJ), K562 cells, Jurkat cells, and BW5147 cells. Other mammalian cell lines are well-known and readily available from the American Type Culture Collection (ATCC) (Manassas, Va., USA) and the National Institute of General Medical Sciences (NIGMS) Human Genetic Cell Repository at the Coriell Cell Repositories (Camden, N.J., USA). Cells or cell lines derived from lung are particularly preferred because they may provide a more native post-translational processing. Particularly preferred are human lung cells.

[0199] Particular details of the transfection, expression and purification of recombinant proteins are well documented and are understood by those of skill in the art. Further details on the various technical aspects of each of the steps used in recombinant production of foreign genes in bacterial cell expression systems can be found in a number of texts and laboratory manuals in the art. See, e.g., Ausubel (1992), supra, Ausubel (1999), supra, Sambrook (1989), supra, and Sambrook (2001), supra, herein incorporated by reference.

[0200] Methods for introducing the vectors and nucleic acids of the present invention into the host cells are well-known in the art; the choice of technique will depend primarily upon the specific vector to be introduced and the host cell chosen.

[0201] Nucleic acid molecules and vectors may be introduced into prokaryotes, such as E. coli, in a number of ways. For instance, phage lambda vectors will typically be packaged using a packaging extract (e.g., Gigapack® packaging extract, Stratagene, La Jolla, Calif., USA), and the packaged virus used to infect E. coli.

[0202] Plasmid vectors will typically be introduced into chemically competent or electrocompetent bacterial cells. E. coli cells can be rendered chemically competent by treatment, e.g., with CaCl₂, or a solution of Mg²⁺, Mn²⁺, Ca²⁺, Rb⁺ or K⁺, dimethyl sulfoxide, dithiothreitol, and hexamine cobalt (III), Hanahan, J. Mol. Biol. 166(4):557-80 (1983), and vectors introduced by heat shock. A wide variety of chemically competent strains are also available commercially (e.g., Epicurian Coli® XL10-Gold® Ultracompetent Cells (Stratagene, La Jolla, Calif., USA); DH5 competent cells (Clontech Laboratories, Palo Alto, Calif., USA); and TOP10 Chemically Competent E. coli Kit (Invitrogen, Carlsbad, Calif., USA)). Bacterial cells can be rendered electrocompetent, that is, competent to take up exogenous DNA by electroporation, by various pre-pulse treatments; vectors are introduced by electroporation followed by subsequent outgrowth in selected media. An extensive series of protocols is provided online in Electroprotocols (BioRad, Richmond, Calif., USA) (http://www.biorad.com/LifeScience/pdf/New_Gene_Pulser.pdf).

[0203] Vectors can be introduced into yeast cells by spheroplasting, treatment with lithium salts, electroporation, or protoplast fusion. Spheroplasts are prepared by the action of hydrolytic enzymes such as snail-gut extract, usually denoted Glusulase, or Zymolyase, an enzyme from Arthrobacter luteus, to remove portions of the cell wall in the presence of osmotic stabilizers, typically 1 M sorbitol. DNA is added to the spheroplasts, and the mixture is co-precipitated with a solution of polyethylene glycol (PEG) and Ca²⁺. Subsequently, the cells are resuspended in a solution of sorbitol, mixed with molten agar and then layered on the surface of a selective plate containing sorbitol.

[0204] For lithium-mediated transformation, yeast cells are treated with lithium acetate, which apparently permeabilizes the cell wall, DNA is added and the cells are co-precipitated with PEG. The cells are exposed to a brief heat shock, washed free of PEG and lithium acetate, and subsequently spread on plates containing ordinary selective medium. Increased frequencies of transformation are obtained by using specially-prepared single-stranded carrier DNA and certain organic solvents. Schiestl et al, Curr. Genet. 16(5-6): 339-46 (1989).

[0205] For electroporation, freshly-grown yeast cultures are typically washed, suspended in an osmotic protectant, such as sorbitol, mixed with DNA, and the cell suspension pulsed in an electroporation device. Subsequently, the cells are spread on the surface of plates containing selective media. Becker et al., Methods Enzymol. 194: 182-187 (1991). The efficiency of transformation by electroporation can be increased over 1 00-fold by using PEG, single-stranded carrier DNA and cells that are in late log-phase of growth. Larger constructs, such as YACs, can be introduced by protoplast fusion.

[0206] Mammalian and insect cells can be directly infected by packaged viral vectors, or transfected by chemical or electrical means. For chemical transfection, DNA can be coprecipitated with CaPO₄ or introduced using liposomal and nonliposomal lipid-based agents. Commercial kits are available for CaPO₄ transfection (CalPhoS™ Mammalian Transfection Kit, Clontech Laboratories, Palo Alto, Calif., USA), and lipid-mediated transfection can be practiced using commercial reagents, such as LIPOFECTAMINE™ 2000, LIPOFECTAMINE™ Reagent, CELLFECTIN® Reagent, and LIPOFECTIN® Reagent (Invitrogen, Carlsbad, Calif., USA), DOTAP Liposomal Transfection Reagent, FuGENE 6, X-tremeGENE Q2, DOSPER, (Roche Molecular Biochemicals, Indianapolis, Iind. USA), Effectene™, PolyFect®, Superfect® (Qiagen, Inc., Valencia, Calif., USA). Protocols for electroporating mammalian cells can be found online in Electroprotocols (Bio-Rad, Richmond, Calif., USA) (http://www.bio-rad.com/LifeScience/pdf/New_Gene_Pulser.pdf); Norton et al. (eds.), Gene Transfer Methods: Introducing DNA into Living Cells and Organisms, BioTechniques Books, Eaton Publishing Co. (2000); incorporated herein by reference in its entirety. Other transfection techniques include transfection by particle bombardment and microinjection. See, e.g., Cheng et al., Proc. Natl. Acad. Sci. USA 90(10): 4455-9 (1993); Yang et al., Proc. Natl. Acad. Sci. USA 87(24): 9568-72 (1990).

[0207] Production of the recombinantly produced proteins of the present invention can optionally be followed by purification.

[0208] Purification of recombinantly expressed proteins is now well by those skilled in the art. See, e.g., Thomer et al. (eds.), Applications of Chimeric Genes and Hybrid Proteins, Part A: Gene Expression and Protein Purification (Methods in Enzymology, Vol. 326), Academic Press (2000); Harbin (ed.), Cloning, Gene Expression and Protein Purification: Experimental Procedures and Process Rationale, Oxford Univ. Press (2001); Marshak et al., Strategies for Protein Purification and Characterization: A Laboratory Course Manual, Cold Spring Harbor Laboratory Press (1996); and Roe (ed.), Protein Purification Applications, Oxford University Press (2001); the disclosures of which are incorporated herein by reference in their entireties, and thus need not be detailed here.

[0209] Briefly, however, if purification tags have been fused through use of an expression vector that appends such tags, purification can be effected, at least in part, by means appropriate to the tag, such as use of immobilized metal affinity chromatography for polyhistidine tags. Other techniques common in the art include ammonium sulfate fractionation, immunoprecipitation, fast protein liquid chromatography (FPLC), high performance liquid chromatography (HPLC), and preparative gel electrophoresis.

[0210] Polypeptides

[0211] Another object of the invention is to provide polypeptides encoded by the nucleic acid molecules of the instant invention. In a preferred embodiment, the polypeptide is a lung specific polypeptide (LSP). In an even more preferred embodiment, the polypeptide is derived from a polypeptide comprising the amino acid sequence of SEQ ID NO: 165 through 284. A polypeptide as defined herein may be produced recombinantly, as discussed supra, may be isolated from a cell that naturally expresses the protein, or may be chemically synthesized following the teachings of the specification and using methods well-known to those having ordinary skill in the art.

[0212] In another aspect, the polypeptide may comprise a fragment of a polypeptide, wherein the fragment is as defined herein. In a preferred embodiment, the polypeptide fragment is a fragment of an LSP. In a more preferred embodiment, the fragment is derived from a polypeptide comprising the amino acid sequence of SEQ ID NO: 165 through 284. A polypeptide that comprises only a fragment of an entire LSP may or may not be a polypeptide that is also an LSP. For instance, a full-length polypeptide may be lung-specific, while a fragment thereof may be found in other tissues as well as in lung. A polypeptide that is not an LSP, whether it is a fragment, analog, mutein, homologous protein or derivative, is nevertheless useful, especially for immunizing animals to prepare anti-LSP antibodies. However, in a preferred embodiment, the part or fragment is an LSP. Methods of determining whether a polypeptide is an LSP are described infra.

[0213] Fragments of at least 6 contiguous amino acids are useful in mapping B cell and T cell epitopes of the reference protein. See, e.g., Geysen et al., Proc. Natl. Acad. Sci. USA 81: 3998-4002 (1984) and U.S. Pat. Nos. 4,708,871 and 5,595,915, the disclosures of which are incorporated herein by reference in their entireties. Because the fragment need not itself be immunogenic, part of an immunodominant epitope, nor even recognized by native antibody, to be useful in such epitope mapping, all fragments of at least 6 amino acids of the proteins of the present invention have utility in such a study.

[0214] Fragments of at least 8 contiguous amino acids, often at least 15 contiguous amino acids, are useful as immunogens for raising antibodies that recognize the proteins of the present invention. See, e.g., Lemer, Nature 299: 592-596 (1982); Shinnick et al., Annu. Rev. Microbiol. 37: 425-46 (1983); Sutcliffe et al., Science 219: 660-6 (1983), the disclosures of which are incorporated herein by reference in their entireties. As further described in the above-cited references, virtually all 8-mers, conjugated to a carrier, such as a protein, prove immunogenic, meaning that they are capable of eliciting antibody for the conjugated peptide; accordingly, all fragments of at least 8 amino acids of the proteins of the present invention have utility as immunogens.

[0215] Fragments of at least 8, 9, 10 or 12 contiguous amino acids are also useful as competitive inhibitors of binding of the entire protein, or a portion thereof, to antibodies (as in epitope mapping), and to natural binding partners, such as subunits in a multimeric complex or to receptors or ligands of the subject protein; this competitive inhibition permits identification and separation of molecules that bind specifically to the protein of interest, U.S. Pat. Nos. 5,539,084 and 5,783,674, incorporated herein by reference in their entireties.

[0216] The protein, or protein fragment, of the present invention is thus at least 6 amino acids in length, typically at least 8, 9, 10 or 12 amino acids in length, and often at least 15 amino acids in length. Often, the protein of the present invention, or fragment thereof, is at least 20 amino acids in length, even 25 amino acids, 30 amino acids, 35 amino acids, or 50 amino acids or more in length. Of course, larger fragments having at least 75 amino acids, 100 amino acids, or even 150 amino acids are also useful, and at times preferred.

[0217] One having ordinary skill in the art can produce fragments of a polypeptide by truncating the nucleic acid molecule, e.g., an LSNA, encoding the polypeptide and then expressing it recombinantly. Alternatively, one can produce a fragment by chemically synthesizing a portion of the full-length polypeptide. One may also produce a fragment by enzymatically cleaving either a recombinant polypeptide or an isolated naturally-occurring polypeptide. Methods of producing polypeptide fragments are well-known in the art. See, e.g., Sambrook (1989), supra; Sambrook (2001), supra; Ausubel (1992), supra; and Ausubel (1999), supra. In one embodiment, a polypeptide comprising only a fragment of polypeptide of the invention, preferably an LSP, may be produced by chemical or enzymatic cleavage of a polypeptide. In a preferred embodiment, a polypeptide fragment is produced by expressing a nucleic acid molecule encoding a fragment of the polypeptide, preferably an LSP, in a host cell.

[0218] By “polypeptides” as used herein it is also meant to be inclusive of mutants, fusion proteins, homologous proteins and allelic variants of the polypeptides specifically exemplified.

[0219] A mutant protein, or mutein, may have the same or different properties compared to a naturally-occurring polypeptide and comprises at least one amino acid insertion, duplication, deletion, rearrangement or substitution compared to the amino acid sequence of a native protein. Small deletions and insertions can often be found that do not alter the flnction of the protein. In one embodiment, the mutein may or may not be lung-specific. In a preferred embodiment, the mutein is lung-specific. In a preferred embodiment, the mutein is a polypeptide that comprises at least one amino acid insertion, duplication, deletion, rearrangement or substitution compared to the amino acid sequence of SEQ ID NO: 165 through 284. In a more preferred embodiment, the mutein is one that exhibits at least 50% sequence identity, more preferably at least 60% sequence identity, even more preferably at least 70%, yet more preferably at least 80% sequence identity to an LSP comprising an amino acid sequence of SEQ ID NO: 165 through 284. In yet a more preferred embodiment, the mutein exhibits at least 85%, more preferably 90%, even more preferably 95% or 96%, and yet more preferably at least 97%, 98%, 99% or 99.5% sequence identity to an LSP comprising an amino acid sequence of SEQ ID NO: 165 through 284.

[0220] A mutein may be produced by isolation from a naturally-occurring mutant cell, tissue or organism. A mutein may be produced by isolation from a cell, tissue or organism that has been experimentally mutagenized. Alternatively, a mutein may be produced by chemical manipulation of a polypeptide, such as by altering the amino acid residue to another amino acid residue using synthetic or semi-synthetic chemical techniques. In a preferred embodiment, a mutein may be produced from a host cell comprising an altered nucleic acid molecule compared to the naturally-occurring nucleic acid molecule. For instance, one may produce a mutein of a polypeptide by introducing one or more mutations into a nucleic acid sequence of the invention and then expressing it recombinantly. These mutations may be targeted, in which particular encoded amino acids are altered, or may be untargeted, in which random encoded amino acids within the polypeptide are altered. Muteins with random amino acid alterations can be screened for a particular biological activity or property, particularly whether the polypeptide is lung-specific, as described below. Multiple random mutations can be introduced into the gene by methods well-known to the art, e.g., by error-prone PCR, shuffling, oligonucleotide-directed mutagenesis, assembly PCR, sexual PCR mutagenesis, in vivo mutagenesis, cassette mutagenesis, recursive ensemble mutagenesis, exponential ensemble mutagenesis and site-specific mutagenesis. Methods of producing muteins with targeted or random amino acid alterations are well-known in the art. See, e.g., Sambrook (1989), supra; Sambrook (2001), supra; Ausubel (1992), supra; and Ausubel (1999), U.S. Pat. No. 5,223,408, and the references discussed supra, each herein incorporated by reference.

[0221] By “polypeptide” as used herein it is also meant to be inclusive of polypeptides homologous to those polypeptides exemplified herein. In a preferred embodiment, the polypeptide is homologous to an LSP. In an even more preferred embodiment, the polypeptide is homologous to an LSP selected from the group having an amino acid sequence of SEQ ID NO: 165 through 284. In a preferred embodiment, the homologous polypeptide is one that exhibits significant sequence identity to an LSP. In a more preferred embodiment, the polypeptide is one that exhibits significant sequence identity to an comprising an amino acid sequence of SEQ ID NO: 165 through 284. In an even more preferred embodiment, the homologous polypeptide is one that exhibits at least 50% sequence identity, more preferably at least 60% sequence identity, even more preferably at least 70%, yet more preferably at least 80% sequence identity to an LSP comprising an amino acid sequence of SEQ ID NO: 165 through 284. In a yet more preferred embodiment, the homologous polypeptide is one that exhibits at least 85%, more preferably 90%, even more preferably 95% or 96%, and yet more preferably at least 97% or 98% sequence identity to an LSP comprising an amino acid sequence of SEQ ID NO: 165 through 284. In another preferred embodiment, the homologous polypeptide is one that exhibits at least 99%, more preferably 99.5%, even more preferably 99.6%, 99.7%, 99.8% or 99.9% sequence identity to an LSP comprising an amino acid sequence of SEQ ID NO: 165 through 284. In a preferred embodiment, the amino acid substitutions are conservative amino acid substitutions as discussed above.

[0222] In another embodiment, the homologous polypeptide is one that is encoded by a nucleic acid molecule that selectively hybridizes to an LSNA. In a preferred embodiment, the homologous polypeptide is encoded by a nucleic acid molecule that hybridizes to an LSNA under low stringency, moderate stringency or high stringency conditions, as defined herein. In a more preferred embodiment, the LSNA is selected from the group consisting of SEQ ID NO: 1 through 164. In another preferred embodiment, the homologous polypeptide is encoded by a nucleic acid molecule that hybridizes to a nucleic acid molecule that encodes an LSP under low stringency, moderate stringency or high stringency conditions, as defined herein. In a more preferred embodiment, the LSP is selected from the group consisting of SEQ ID NO: 165 through 284.

[0223] The homologous polypeptide may be a naturally-occurring one that is derived from another species, especially one derived from another primate, such as chimpanzee, gorilla, rhesus macaque, baboon or gorilla, wherein the homologous polypeptide comprises an amino acid sequence that exhibits significant sequence identity to that of SEQ ID NO: 165 through 284. The homologous polypeptide may also be a naturally-occurring polypeptide from a human, when the LSP is a member of a family of polypeptides. The homologous polypeptide may also be a naturally-occurring polypeptide derived from a non-primate, mammalian species, including without limitation, domesticated species, e.g., dog, cat, mouse, rat, rabbit, guinea pig, hamster, cow, horse, goat or pig. The homologous polypeptide may also be a naturally-occurring polypeptide derived from a non-mammalian species, such as birds or reptiles. The naturally-occurring homologous protein may be isolated directly from humans or other species. Alternatively, the nucleic acid molecule encoding the naturally-occurring homologous polypeptide may be isolated and used to express the homologous polypeptide recombinantly. In another embodiment, the homologous polypeptide may be one that is experimentally produced by random mutation of a nucleic acid molecule and subsequent expression of the nucleic acid molecule. In another embodiment, the homologous polypeptide may be one that is experimentally produced by directed mutation of one or more codons to alter the encoded amino acid of an LSP. Further, the homologous protein may or may not encode polypeptide that is an LSP. However, in a preferred embodiment, the homologous polypeptide encodes a polypeptide that is an LSP.

[0224] Relatedness of proteins can also be characterized using a second functional test, the ability of a first protein competitively to inhibit the binding of a second protein to an antibody. It is, therefore, another aspect of the present invention to provide isolated proteins not only identical in sequence to those described with particularity herein, but also to provide isolated proteins (“cross-reactive proteins”) that competitively inhibit the binding of antibodies to all or to a portion of various of the isolated polypeptides of the present invention. Such competitive inhibition can readily be determined using immunoassays well-known in the art.

[0225] As discussed above, single nucleotide polymorphisms (SNPs) occur frequently in eukaryotic genomes, and the sequence determined from one individual of a species may differ from other allelic forms present within the population. Thus, by “polypeptide” as used herein it is also meant to be inclusive of polypeptides encoded by an allelic variant of a nucleic acid molecule encoding an LSP. In a preferred embodiment, the polypeptide is encoded by an allelic variant of a gene that encodes a polypeptide having the amino acid sequence selected from the group consisting of SEQ ID NO: 165 through 284. In a yet more preferred embodiment, the polypeptide is encoded by an allelic variant of a gene that has the nucleic acid sequence selected from the group consisting of SEQ ID NO: 1 through 164.

[0226] In another embodiment, the invention provides polypeptides which comprise derivatives of a polypeptide encoded by a nucleic acid molecule according to the instant invention. In a preferred embodiment, the polypeptide is an LSP. In a preferred embodiment, the polypeptide has an amino acid sequence selected from the group consisting of SEQ ID NO: 165 through 284, or is a mutein, allelic variant, homologous protein or fragment thereof. In a preferred embodiment, the derivative has been acetylated, carboxylated, phosphorylated, glycosylated or ubiquitinated. In another preferred embodiment, the derivative has been labeled with, e.g., radioactive isotopes such as ¹²⁵I, ³²P, ³⁵%, and ³H. In another preferred embodiment, the derivative has been labeled with fluorophores, chemiluminescent agents, enzymes, and antiligands that can serve as specific binding pair members for a labeled ligand.

[0227] Polypeptide modifications are well-known to those of skill and have been described in great detail in the scientific literature. Several particularly common modifications, glycosylation, lipid attachment, sulfation, gamma-carboxylation of glutamic acid residues, hydroxylation and ADP-ribosylation, for instance, are described in most basic texts, such as, for instance Creighton, Protein Structure and Molecular Properties, 2nd ed., W. H. Freeman and Company (1993). Many detailed reviews are available on this subject, such as, for example, those provided by Wold, in Johnson (ed.), Posttranslational Covalent Modification of Proteins, pgs. 1-12, Academic Press (1983); Seifter et al., Meth. Enzymol. 182: 626-646 (1990) and Rattan et al., Ann. N.Y. Acad. Sci. 663: 48-62 (1992).

[0228] It will be appreciated, as is well-known and as noted above, that polypeptides are not always entirely linear. For instance, polypeptides may be branched as a result of ubiquitination, and they may be circular, with or without branching, generally as a result of posttranslation events, including natural processing event and events brought about by human manipulation which do not occur naturally. Circular, branched and branched circular polypeptides may be synthesized by non-translation natural process and by entirely synthetic methods, as well. Modifications can occur anywhere in a polypeptide, including the peptide backbone, the amino acid side-chains and the amino or carboxyl termini. In fact, blockage of the amino or carboxyl group in a polypeptide, or both, by a covalent modification, is common in naturally occurring and synthetic polypeptides and such modifications may be present in polypeptides of the present invention, as well. For instance, the amino terminal residue of polypeptides made in E. coli, prior to proteolytic processing, almost invariably will be N-formylmethionine.

[0229] Useful post-synthetic (and post-translational) modifications include conjugation to detectable labels, such as fluorophores. A wide variety of amine-reactive and thiol-reactive fluorophore derivatives have been synthesized that react under nondenaturing conditions with N-terminal amino groups and epsilon amino groups of lysine residues, on the one hand, and with free thiol groups of cysteine residues, on the other.

[0230] Kits are available commercially that permit conjugation of proteins to a variety of amine-reactive or thiol-reactive fluorophores: Molecular Probes, Inc. (Eugene, Oreg., USA), e.g., offers kits for conjugating proteins to Alexa Fluor 350, Alexa Fluor 430, Fluorescein-EX, Alexa Fluor 488, Oregon Green 488, Alexa Fluor 532, Alexa Fluor 546, Alexa Fluor 546, Alexa Fluor 568, Alexa Fluor 594, and Texas Red-X.

[0231] A wide variety of other amine-reactive and thiol-reactive fluorophores are available commercially (Molecular Probes, Inc., Eugene, Oreg., USA), including Alexa Fluor® 350, Alexa Fluor® 488, Alexa Fluor® 532, Alexa Fluor® 546, Alexa Fluor® 568, Alexa Fluor® 594, Alexa Fluor® 647 (monoclonal antibody labeling kits available from Molecular Probes, Inc., Eugene, Oreg., USA), BODIPY dyes, such as BODIPY 493/503, BODIPY FL, BODIPY R6G, BODIPY 530/550, BODIPY TMR, BODIPY 558/568, BODIPY 558/568, BODIPY 564/570, BODIPY 576/589, BODIPY 581/591, BODIPY TR, BODIPY 630/650, BODIPY 650/665, Cascade Blue, Cascade Yellow, Dansyl, lissamine rhodamine B, Marina Blue, Oregon Green 488, Oregon Green 514, Pacific Blue, rhodamine 6G, rhodamine green, rhodamine red, tetramethylrhodamine, Texas Red (available from Molecular Probes, Inc., Eugene, Oreg., USA).

[0232] The polypeptides of the present invention can also be conjugated to fluorophores, other proteins, and other macromolecules, using bifunctional linking reagents. Common homobifunctional reagents include, e.g., APG, AEDP, BASED, BMB, BMDB, BMH, BMOE, BM[PEO]3, BM[PEO]4, BS3, BSOCOES, DFDNB, DMA, DMP, DMS, DPDPB, DSG, DSP (Lomant's Reagent), DSS, DST, DTBP, DTME, DTSSP, EGS, HBVS, Sulfo-BSOCOES, Sulfo-DST, Sulfo-EGS (all available from Pierce, Rockford, Ill., USA); common heterobifunctional cross-linkers include ABH, AMAS, ANB-NOS, APDP, ASBA, BMPA, BMPH, BMPS, EDC, EMCA, EMCH, EMCS, KMUA, KMUH, GMBS, LC-SMCC, LC-SPDP, MBS, M2C2H, MPBH, MSA, NHS-ASA, PDPH, PMPI, SADP, SAED, SAND, SANPAH, SASD, SATP, SBAP, SFAD, SIA, SIAB, SMCC, SMPB, SMPH, SMPT, SPDP, Sulfo-EMCS, Sulfo-GMBS, Sulfo-HSAB, Sulfo-KMUS, Sulfo-LC-SPDP, Sulfo-MBS, Sulfo-NHS-LC-ASA, Sulfo-SADP, Sulfo-SANPAH, Sulfo-SIAB, Sulfo-SMCC, Sulfo-SMPB, Sulfo-LC-SMPT, SVSB, TFCS (all available Pierce, Rockford, Ill., USA).

[0233] The polypeptides, fragments, and fusion proteins of the present invention can be conjugated, using such cross-linking reagents, to fluorophores that are not amine- or thiol-reactive. Other labels that usefully can be conjugated to the polypeptides, fragments, and fusion proteins of the present invention include radioactive labels, echosonographic contrast reagents, and MRI contrast agents.

[0234] The polypeptides, fragments, and fusion proteins of the present invention can also usefully be conjugated using cross-linking agents to carrier proteins, such as KLH, bovine thyroglobulin, and even bovine serum albumin (BSA), to increase immunogenicity for raising anti-LSP antibodies.

[0235] The polypeptides, fragments, and fusion proteins of the present invention can also usefully be conjugated to polyethylene glycol (PEG); PEGylation increases the serum half-life of proteins administered intravenously for replacement therapy. Delgado et al., Crit. Rev. Ther. Drug Carrier Syst. 9(3-4): 249-304 (1992); Scott et al., Curr. Pharm. Des. 4(6): 423-38 (1998); DeSantis et al., Curr. Opin. Biotechnol. 10(4): 324-30 (1999), incorporated herein by reference in their entireties. PEG monomers can be attached to the protein directly or through a linker, with PEGylation using PEG monomers activated with tresyl chloride (2,2,2-trifluoroethanesulphonyl chloride) permitting direct attachment under mild conditions.

[0236] In yet another embodiment, the invention provides analogs of a polypeptide encoded by a nucleic acid molecule according to the instant invention. In a preferred embodiment, the polypeptide is an LSP. In a more preferred embodiment, the analog is derived from a polypeptide having part or all of the amino acid sequence of SEQ ID NO: 165 through 284. In a preferred embodiment, the analog is one that comprises one or more substitutions of non-natural amino acids or non-native inter-residue bonds compared to the naturally-occurring polypeptide. In general, the non-peptide analog is structurally similar to an LSP, but one or more peptide linkages is replaced by a linkage selected from the group consisting of —CH₂NH—, —CH₂S—, —CH₂—CH₂—, —CH═CH—(cis and trans), —COCH₂—, —CH(OH)CH₂—and —CH₂SO—. In another embodiment, the non-peptide analog comprises substitution of one or more amino acids of an LSP with a D-amino acid of the same type or other non-natural amino acid in order to generate more stable peptides. D-amino acids can readily be incorporated during chemical peptide synthesis: peptides assembled from D-amino acids are more resistant to proteolytic attack; incorporation of D-amino acids can also be used to confer specific three-dimensional conformations on the peptide. Other amino acid analogues commonly added during chemical synthesis include omithine, norleucine, phosphorylated amino acids (typically phosphoserine, phosphothreonine, pho sphotyro sine), L-malonyltyro sine, a non-hydrolyzable analog of phosphotyrosine (see, e.g., Kole et al., Biochem. Biophys. Res. Com. 209: 817-821 (1995)), and various halogenated phenylalanine derivatives.

[0237] Non-natural amino acids can be incorporated during solid phase chemical synthesis or by recombinant techniques, although the former is typically more common. Solid phase chemical synthesis of peptides is well established in the art. Procedures are described, inter alia, in Chan et al. (eds.), Fmoc Solid Phase Peptide Synthesis: A Practical Approach (Practical Approach Series), Oxford Univ. Press (March 2000); Jones, Amino Acid and Peptide Synthesis (Oxford Chemistry Primers, No 7), Oxford Univ. Press (1992); and Bodanszky, Principles of Peptide Synthesis (Springer Laboratory), Springer Verlag (1993); the disclosures of which are incorporated herein by reference in their entireties.

[0238] Amino acid analogues having detectable labels are also usefully incorporated during synthesis to provide derivatives and analogs. Biotin, for example can be added using biotinoyl-(9-fluorenylmethoxycarbonyl)-L-lysine (FMOC biocytin) (Molecular Probes, Eugene, Oreg., USA). Biotin can also be added enzymatically by incorporation into a fusion protein of a E. coli BirA substrate peptide. The FMOC and tBOC derivatives of dabcyl-L-lysine (Molecular Probes, Inc., Eugene, Oreg., USA) can be used to incorporate the dabcyl chromophore at selected sites in the peptide sequence during synthesis. The aminonaphthalene derivative EDANS, the most common fluorophore for pairing with the dabcyl quencher in fluorescence resonance energy transfer (FRET) systems, can be introduced during automated synthesis of peptides by using EDANS-FMOC-L-glutamic acid or the corresponding tBOC derivative (both from Molecular Probes, Inc., Eugene, Oreg., USA). Tetramethylrhodamine fluorophores can be incorporated during automated FMOC synthesis of peptides using (FMOC)-TMR-L-lysine (Molecular Probes, Inc. Eugene, Oreg., USA).

[0239] Other useful amino acid analogues that can be incorporated during chemical synthesis include aspartic acid, glutamic acid, lysine, and tyrosine analogues having allyl side-chain protection (Applied Biosystems, Inc., Foster City, Calif., USA); the allyl side chain permits synthesis of cyclic, branched-chain, sulfonated, glycosylated, and phosphorylated peptides.

[0240] A large number of other FMOC-protected non-natural amino acid analogues capable of incorporation during chemical synthesis are available commercially, including, e.g., Fmoc-2-aminobicyclo[2.2.1]heptane-2-carboxylic acid, Fmoc-3-endo-aminobicyclo[2.2.1]heptane-2-endo-carboxylic acid, Fmoc-3-exo-aminobicyclo[2.2.1]heptane-2-exo-carboxylic acid, Fmoc-3-endo-amino-bicyclo[2.2. 1 ]hept-5-ene-2-endo-carboxylic acid, Fmoc-3-exo-amino-bicyclo[2.2.1 ]hept-5-ene-2-exo-carboxylic acid, Fmoc-cis-2-amino-1-cyclohexanecarboxylic acid, Fmoc-trans-2-amino-1-cyclohexanecarboxylic acid, Fmoc-1-amino-1-cyclopentanecarboxylic acid, Fmoc-cis-2-amino-1-cyclopentanecarboxylic acid, Fmoc-1-amino-1-cyclopropanecarboxylic acid, Fmoc-D-2-amino-4-(ethylthio)butyric acid, Fmoc-L-2-amino-4-(ethylthio)butyric acid, Fmoc-L-buthionine, Fmoc-S-methyl-L-Cysteine, Fmoc-2-aminobenzoic acid (anthranillic acid), Fmoc-3-aminobenzoic acid, Fmoc-4-aminobenzoic acid, Fmoc-2-aminobenzophenone-2′-carboxylic acid, Fmoc-N-(4-aminobenzoyl)-β-alanine, Fmoc-2-amino-4,5-dimethoxybenzoic acid, Fmoc-4-aminohippuric acid, Fmoc-2-amino-3-hydroxybenzoic acid, Fmoc-2-amino-5-hydroxybenzoic acid, Fmoc-3-amino-4-hydroxybenzoic acid, Fmoc-4-amino-3-hydroxybenzoic acid, Fmoc-4-amino-2-hydroxybenzoic acid, Fmoc-5-amino-2-hydroxybenzoic acid, Fmoc-2-amino-3-methoxybenzoic acid, Fmoc-4-amino-3-methoxybenzoic acid, Fmoc-2-amino-3-methylbenzoic acid, Fmoc-2-amino-5-methylbenzoic acid, Fmoc-2-amino-6-methylbenzoic acid, Fmoc-3-amino-2-methylbenzoic acid, Fmoc-3-amino-4-methylbenzoic acid, Fmoc-4-amino-3-methylbenzoic acid, Fmoc-3-amino-2-naphtoic acid, Fmoc-D,L-3-amino-3-phenylpropionic acid, Fmoc-L-Methyldopa, Fmoc-2-amino-4,6-dimethyl-3-pyridinecarboxylic acid, Fmoc-D,L-amino-2-thiophenacetic acid, Fmoc-4-(carboxymethyl)piperazine, Fmoc-4-carboxypiperazine, Fmoc-4-(carboxymethyl)homopiperazine, Fmoc-4-phenyl-4-piperidinecarboxylic acid, Fmoc-L-1,2,3,4-tetrahydronorharman-3-carboxylic acid, Fmoc-L-thiazolidine-4-carboxylic acid, all available from The Peptide Laboratory (Richmond, Calif., USA).

[0241] Non-natural residues can also be added biosynthetically by engineering a suppressor tRNA, typically one that recognizes the UAG stop codon, by chemical aminoacylation with the desired unnatural amino acid. Conventional site-directed mutagenesis is used to introduce the chosen stop codon UAG at the site of interest in the protein gene. When the acylated suppressor tRNA and the mutant gene are combined in an in vitro transcription/translation system, the unnatural amino acid is incorporated in response to the UAG codon to give a protein containing that amino acid at the specified position. Liu et al., Proc. Natl Acad. Sci. USA 96(9): 4780-5 (1999); Wang et al., Science 292(5516): 498-500 (2001).

[0242] Fusion Proteins

[0243] The present invention further provides fusions of each of the polypeptides and fragments of the present invention to heterologous polypeptides. In a preferred embodiment, the polypeptide is an LSP. In a more preferred embodiment, the polypeptide that is fused to the heterologous polypeptide comprises part or all of the amino acid sequence of SEQ ID NO: 165 through 284, or is a mutein, homologous polypeptide, analog or derivative thereof. In an even more preferred embodiment, the nucleic acid molecule encoding the fusion protein comprises all or part of the nucleic acid sequence of SEQ ID NO: 1 through 164, or comprises all or part of a nucleic acid sequence that selectively hybridizes or is homologous to a nucleic acid molecule comprising a nucleic acid sequence of SEQ ID NO: 1 through 164.

[0244] The fusion proteins of the present invention will include at least one fragment of the protein of the present invention, which fragment is at least 6, typically at least 8, often at least 15, and usefully at least 16, 17, 18, 19, or 20 amino acids long. The fragment of the protein of the present to be included in the fusion can usefully be at least 25 amino acids long, at least 50 amino acids long, and can be at least 75, 100, or even 150 amino acids long. Fusions that include the entirety of the proteins of the present invention have particular utility.

[0245] The heterologous polypeptide included within the fusion protein of the present invention is at least 6 amino acids in length, often at least 8 amino acids in length, and usefully at least 15, 20, and 25 amino acids in length. Fusions that include larger polypeptides, such as the IgG Fc region, and even entire proteins (such as GFP chromophore-containing proteins) are particular useful.

[0246] As described above in the description of vectors and expression vectors of the present invention, which discussion is incorporated here by reference in its entirety, heterologous polypeptides to be included in the fusion proteins of the present invention can usefully include those designed to facilitate purification and/or visualization of recombinantly-expressed proteins. See, e.g., Ausubel, Chapter 16, (1992), supra. Although purification tags can also be incorporated into fusions that are chemically synthesized, chemical synthesis typically provides sufficient purity that further purification by HPLC suffices; however, visualization tags as above described retain their utility even when the protein is produced by chemical synthesis, and when so included render the fusion proteins of the present invention useful as directly detectable markers of the presence of a polypeptide of the invention.

[0247] As also discussed above, heterologous polypeptides to be included in the fusion proteins of the present invention can usefully include those that facilitate secretion of recombinantly expressed proteins—into the periplasmic space or extracellular milieu for prokaryotic hosts, into the culture medium for eukaryotic cells—through incorporation of secretion signals and/or leader sequences. For example, a His⁶ tagged protein can be purified on a Ni affinity column and a GST fusion protein can be purified on a glutathione affinity column. Similarly, a fusion protein comprising the Fc domain of IgG can be purified on a Protein A or Protein G column and a fusion protein comprising an epitope tag such as myc can be purified using an immunoaffinity column containing an anti-c-myc antibody. It is preferable that the epitope tag be separated from the protein encoded by the essential gene by an enzymatic cleavage site that can be cleaved after purification. See also the discussion of nucleic acid molecules encoding fusion proteins that may be expressed on the surface of a cell.

[0248] Other useful protein fusions of the present invention include those that permit use of the protein of the present invention as bait in a yeast two-hybrid system. See Bartel et al. (eds.), The Yeast Two-Hybrid System, Oxford University Press (1997); Zhu et al., Yeast Hybrid Technologies, Eaton Publishing (2000); Fields et al., Trends Genet. 10(8): 286-92 (1994); Mendelsohn et al., Curr. Opin. BiotechnoL 5(5): 482-6 (1994); Luban et al., Curr. Opin. Biotechnol. 6(1): 59-64 (1995); Allen et al., Trends Biochem. Sci. 20(12): 511-6 (1995); Drees, Curr. Opin. Chem. Biol. 3(1): 64-70 (1999); Topcu et al., Pharm. Res. 17(9): 1049-55 (2000); Fashena et al., Gene 250(1-2): 1-14 (2000); Colas et al., (1996) Genetic selection of peptide aptamers that recognize and inhibit cyclin-dependent kinase 2. Nature 380, 548-550; Norman, T. et al., (1999) Genetic selection of peptide inhibitors of biological pathways. Science 285, 591-595, Fabbrizio et al., (1999) Inhibition of mammalian cell proliferation by genetically selected peptide aptamers that functionally antagonize E2F activity. Oncogene 18, 4357-4363; Xu et al., (1997) Cells that register logical relationships among proteins. Proc Natl Acad Sci USA. 94, 12473-12478; Yang, et al., (1995) Protein-peptide interactions analyzed with the yeast two-hybrid system. Nuc. Acids Res. 23, 1152-1156; Kolonin et al., (1998) Targeting cyclin-dependent kinases in Drosophila with peptide aptamers. Proc Natl Acad Sci USA 95, 14266-14271; Cohen et al., (1998) An artificial cell-cycle inhibitor isolated from a combinatorial library. Proc Natl Acad Sci U S A 95, 14272-14277; Uetz, P.; Giot, L.; al, e.; Fields, S.; Rothberg, J. M. (2000) A comprehensive analysis of protein-protein interactions in Saccharomyces cerevisiae. Nature 403, 623-627; Ito, et al., (2001) A comprehensive two-hybrid analysis to explore the yeast protein interactome. Proc Natl Acad Sci USA 98, 4569-4574, the disclosures of which are incorporated herein by reference in their entireties. Typically, such fusion is to either E. coli LexA or yeast GAL4 DNA binding domains. Related bait plasmids are available that express the bait fused to a nuclear localization signal.

[0249] Other useful fusion proteins include those that permit display of the encoded protein on the surface of a phage or cell, fusions to intrinsically fluorescent proteins, such as green fluorescent protein (GFP), and fusions to the IgG Fc region, as described above, which discussion is incorporated here by reference in its entirety.

[0250] The polypeptides and fragments of the present invention can also usefully be fused to protein toxins, such as Pseudomonas exotoxin A, diphtheria toxin, shiga toxin A, anthrax toxin lethal factor, ricin, in order to effect ablation of cells that bind or take up the proteins of the present invention.

[0251] Fusion partners include, inter alia, myc, hemagglutinin (HA), GST, immunoglobulins, β-galactosidase, biotin trpE, protein A, β-lactamase, -amylase, maltose binding protein, alcohol dehydrogenase, polyhistidine (for example, six histidine at the amino and/or carboxyl terminus of the polypeptide), lacZ, green fluorescent protein (GFP), yeast_mating factor, GAL4 transcription activation or DNA binding domain, luciferase, and serum proteins such as ovalbumin, albumin and the constant domain of IgG. See, e.g., Ausubel (1992), supra and Ausubel (1999), supra. Fusion proteins may also contain sites for specific enzymatic cleavage, such as a site that is recognized by enzymes such as Factor XIII, trypsin, pepsin, or any other enzyme known in the art. Fusion proteins will typically be made by either recombinant nucleic acid methods, as described above, chemically synthesized using techniques well-known in the art (e.g., a Merrifield synthesis), or produced by chemical cross-linking.

[0252] Another advantage of fusion proteins is that the epitope tag can be used to bind the fusion protein to a plate or column through an affinity linkage for screening binding proteins or other molecules that bind to the LSP.

[0253] As further described below, the isolated polypeptides, muteins, fusion proteins, homologous proteins or allelic variants of the present invention can readily be used as specific immunogens to raise antibodies that specifically recognize LSPs, their allelic variants and homologues. The antibodies, in turn, can be used, inter alia, specifically to assay for the polypeptides of the present invention, particularly LSPs, e.g. by ELISA for detection of protein fluid samples, such as serum, by immunohistochemistry or laser scanning cytometry, for detection of protein in tissue samples, or by flow cytometry, for detection of intracellular protein in cell suspensions, for specific antibody-mediated isolation and/or purification of LSPs, as for example by immunoprecipitation, and for use as specific agonists or antagonists of LSPs.

[0254] One may determine whether polypeptides including muteins, fusion proteins, homologous proteins or allelic variants are functional by methods known in the art. For instance, residues that are tolerant of change while retaining function can be identified by altering the protein at known residues using methods known in the art, such as alanine scanning mutagenesis, Cunningham et al., Science 244(4908): 1081-5 (1989); transposon linker scanning mutagenesis, Chen et al., Gene 263(1-2): 39-48 (2001); combinations of homolog- and alanine-scanning mutagenesis, Jin et al., J. Mol. Biol. 226(3): 851-65 (1992); combinatorial alanine scanning, Weiss et al, Proc. Natl. Acad. Sci USA 97(16): 8950-4 (2000), followed by functional assay. Transposon linker scanning kits are available commercially (New England Biolabs, Beverly, Mass., USA, catalog. no. E7-102S; EZ::TN™ In-Frame Linker Insertion Kit, catalogue no. EZI04KN, Epicentre Technologies Corporation, Madison, Wis., USA).

[0255] Purification of the polypeptides including fragments, homologous polypeptides, muteins, analogs, derivatives and fusion proteins is well-known and within the skill of one having ordinary skill in the art. See, e.g., Scopes, Protein Purification, 2d ed. (1987). Purification of recombinantly expressed polypeptides is described above. Purification of chemically-synthesized peptides can readily be effected, e.g., by HPLC.

[0256] Accordingly, it is an aspect of the present invention to provide the isolated proteins of the present invention in pure or substantially pure form in the presence of absence of a stabilizing agent. Stabilizing agents include both proteinaceous or non-proteinaceous material and are well-known in the art. Stabilizing agents, such as albumin and polyethylene glycol (PEG) are known and are commercially available.

[0257] Although high levels of purity are preferred when the isolated proteins of the present invention are used as therapeutic agents, such as in vaccines and as replacement therapy, the isolated proteins of the present invention are also useful at lower purity. For example, partially purified proteins of the present invention can be used as immunogens to raise antibodies in laboratory animals.

[0258] In preferred embodiments, the purified and substantially purified proteins of the present invention are in compositions that lack detectable ampholytes, acrylamide monomers, bis-acrylamide monomers, and polyacrylamide.

[0259] The polypeptides, fragments, analogs, derivatives and fusions of the present invention can usefully be attached to a substrate. The substrate can be porous or solid, planar or non-planar; the bond can be covalent or noncovalent.

[0260] For example, the polypeptides, fragments, analogs, derivatives and fusions of the present invention can usefully be bound to a porous substrate, commonly a membrane, typically comprising nitrocellulose, polyvinylidene fluoride (PVDF), or cationically derivatized, hydrophilic PVDF; so bound, the proteins, fragments, and fusions of the present invention can be used to detect and quantify antibodies, e.g. in serum, that bind specifically to the immobilized protein of the present invention.

[0261] As another example, the polypeptides, fragments, analogs, derivatives and fusions of the present invention can usefully be bound to a substantially nonporous substrate, such as plastic, to detect and quantify antibodies, e.g. in serum, that bind specifically to the immobilized protein of the present invention. Such plastics include polymethylacrylic, polyethylene, polypropylene, polyacrylate, polymethylmethacrylate, polyvinylchloride, polytetrafluoroethylene, polystyrene, polycarbonate, polyacetal, polysulfone, celluloseacetate, cellulosenitrate, nitrocellulose, or mixtures thereof, when the assay is performed in a standard microtiter dish, the plastic is typically polystyrene.

[0262] The polypeptides, fragments, analogs, derivatives and fusions of the present invention can also be attached to a substrate suitable for use as a surface enhanced laser desorption ionization source; so attached, the protein, fragment, or fusion of the present invention is useful for binding and then detecting secondary proteins that bind with sufficient affinity or avidity to the surface-bound protein to indicate biologic interaction there between. The proteins, fragments, and fusions of the present invention can also be attached to a substrate suitable for use in surface plasmon resonance detection; so attached, the protein, fragment, or fusion of the present invention is useful for binding and then detecting secondary proteins that bind with sufficient affinity or avidity to the surface-bound protein to indicate biological interaction there between.

[0263] Antibodies

[0264] In another aspect, the invention provides antibodies, including fragments and derivatives thereof, that bind specifically to polypeptides encoded by the nucleic acid molecules of the invention, as well as antibodies that bind to fragments, muteins, derivatives and analogs of the polypeptides. In a preferred embodiment, the antibodies are specific for a polypeptide that is an LSP, or a fragment, mutein, derivative, analog or fusion protein thereof. In a more preferred embodiment, the antibodies are specific for a polypeptide that comprises SEQ ID NO: 165 through 284, or a fragment, mutein, derivative, analog or fusion protein thereof.

[0265] The antibodies of the present invention can be specific for linear epitopes, discontinuous epitopes, or conformational epitopes of such proteins or protein fragments, either as present on the protein in its native conformation or, in some cases, as present on the proteins as denatured, as, e.g., by solubilization in SDS. New epitopes may be also due to a difference in post translational modifications (PTMs) in disease versus normal tissue. For example, a particular site on a LSP may be glycosylated in cancerous cells, but not glycosylated in normal cells or visa versa. In addition, alternative splice forms of a LSP may be indicative of cancer. Differential degradation of the C or N-terminus of a LSP may also be a marker or target for anticancer therapy. For example, a LSP may be N-terminal degraded in cancer cells exposing new epitopes to which antibodies may selectively bind for diagnostic or therapeutic uses.

[0266] As is well-known in the art, the degree to which an antibody can discriminate as among molecular species in a mixture will depend, in part, upon the conformational relatedness of the species in the mixture; typically, the antibodies of the present invention will discriminate over adventitious binding to non-LSP polypeptides by at least 2-fold, more typically by at least 5-fold, typically by more than 10-fold, 25-fold, 50-fold, 75-fold, and often by more than 100-fold, and on occasion by more than 500-fold or 1000-fold. When used to detect the proteins or protein fragments of the present invention, the antibody of the present invention is sufficiently specific when it can be used to determine the presence of the protein of the present invention in samples derived from human lung.

[0267] Typically, the affinity or avidity of an antibody (or antibody multimer, as in the case of an IgM pentamer) of the present invention for a protein or protein fragment of the present invention will be at least about 1×10⁻⁶ molar (M), typically at least about 5×10⁻7M, 1×10⁻⁷M, with affinities and avidities of at least 1×10⁻⁸M, 5×10⁻⁹M, 1×10⁻¹⁰M and up to 1×10⁻¹³M proving especially useful.

[0268] The antibodies of the present invention can be naturally-occurring forms, such as IgG, IgM, IgD, IgE, IgY, and IgA, from any avian, reptilian, or mammalian species.

[0269] Human antibodies can, but will infrequently, be drawn directly from human donors or human cells. In this case, antibodies to the proteins of the present invention will typically have resulted from fortuitous immunization, such as autoimmune immunization, with the protein or protein fragments of the present invention. Such antibodies will typically, but will not invariably, be polyclonal. In addition, individual polyclonal antibodies may be isolated and cloned to generate monoclonals.

[0270] Human antibodies are more frequently obtained using transgenic animals that express human immunoglobulin genes, which transgenic animals can be affirmatively immunized with the protein immunogen of the present invention. Human Ig-transgenic mice capable of producing human antibodies and methods of producing human antibodies therefrom upon specific immunization are described, inter alia, in U.S. Pat. Nos. 6,162,963; 6,150,584; 6,114,598; 6,075,181; 5,939,598; 5,877,397; 5,874,299; 5,814,318; 5,789,650; 5,770,429; 5,661,016; 5,633,425; 5,625,126; 5,569,825; 5,545,807; 5,545,806, and 5,591,669, the disclosures of which are incorporated herein by reference in their entireties. Such antibodies are typically monoclonal, and are typically produced using techniques developed for production of murine antibodies.

[0271] Human antibodies are particularly useful, and often preferred, when the antibodies of the present invention are to be administered to human beings as in vivo diagnostic or therapeutic agents, since recipient immune response to the administered antibody will often be substantially less than that occasioned by administration of an antibody derived from another species, such as mouse.

[0272] IgG, IgM, IgD, IgE, IgY, and IgA antibodies of the present invention can also be obtained from other species, including mammals such as rodents (typically mouse, but also rat, guinea pig, and hamster) lagomorphs, typically rabbits, and also larger mammals, such as sheep, goats, cows, and horses, and other egg laying birds or reptiles such as chickens or alligators. For example, avian antibodies may be generated using techniques described in WO 00/29444, published May 25, 2000, the contents of which are hereby incorporated in their entirety. In such cases, as with the transgenic human-antibody-producing non-human mammals, fortuitous immunization is not required, and the non-human mammal is typically affirmatively immunized, according to standard immunization protocols, with the protein or protein fragment of the present invention.

[0273] As discussed above, virtually all fragments of 8 or more contiguous amino acids of the proteins of the present invention can be used effectively as immunogens when conjugated to a carrier, typically a protein such as bovine thyroglobulin, keyhole limpet hemocyanin, or bovine serum albumin, conveniently using a bifunctional linker such as those described elsewhere above, which discussion is incorporated by reference here.

[0274] Immunogenicity can also be conferred by fusion of the polypeptide and fragments of the present invention to other moieties. For example, peptides of the present invention can be produced by solid phase synthesis on a branched polylysine core matrix; these multiple antigenic peptides (MAPs) provide high purity, increased avidity, accurate chemical definition and improved safety in vaccine development. Tam et al., Proc. Natl. Acad. Sci. USA 85: 5409-5413 (1988); Posnett et al., J. Biol. Chem. 263: 1719-1725 (1988).

[0275] Protocols for immunizing non-human mammals or avian species are well-established in the art. See Harlow et al. (eds.), Using Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory (1998); Coligan et al. (eds.), Current Protocols in Immunology, John Wiley & Sons, Inc. (2001); Zola, Monoclonal Antibodies: Preparation and Use of Monoclonal Antibodies and Engineered Antibody Derivatives (Basics: From Background to Bench), Springer Verlag (2000); Gross M, Speck J.Dtsch. Tierarztl. Wochenschr. 103: 417-422 (1996), the disclosures of which are incorporated herein by reference. Immunization protocols often include multiple immunizations, either with or without adjuvants such as Freund's complete adjuvant and Freund's incomplete adjuvant, and may include naked DNA immunization (Moss, Semin. Immunol. 2: 317-327 (1990).

[0276] Antibodies from non-human mammals and avian species can be polyclonal or monoclonal, with polyclonal antibodies having certain advantages in immunohistochemical detection of the proteins of the present invention and monoclonal antibodies having advantages in identifying and distinguishing particular epitopes of the proteins of the present invention. Antibodies from avian species may have particular advantage in detection of the proteins of the present invention, in human serum or tissues (Vikinge et al., Biosens. Bioelectron. 13: 1257-1262 (1998).

[0277] Following immunization, the antibodies of the present invention can be produced using any art-accepted technique. Such techniques are well-known in the art, Coligan, supra; Zola, supra; Howard et al. (eds.), Basic Methods in Antibody Production and Characterization, CRC Press (2000); Harlow, supra; Davis (ed.), Monoclonal Antibody Protocols, Vol. 45, Humana Press (1995); Delves (ed.), Antibody Production: Essential Techniques, John Wiley & Son Ltd (1997); Kenney, Antibody Solution: An Antibody Methods Manual, Chapman & Hall (1997), incorporated herein by reference in their entireties, and thus need not be detailed here.

[0278] Briefly, however, such techniques include, inter alia, production of monoclonal antibodies by hybridomas and expression of antibodies or fragments or derivatives thereof from host cells engineered to express immunoglobulin genes or fragments thereof. These two methods of production are not mutually exclusive: genes encoding antibodies specific for the proteins or protein fragments of the present invention can be cloned from hybridomas and thereafter expressed in other host cells. Nor need the two necessarily be performed together: e.g., genes encoding antibodies specific for the proteins and protein fragments of the present invention can be cloned directly from B cells known to be specific for the desired protein, as further described in U.S Pat. No. 5,627,052, the disclosure of which is incorporated herein by reference in its entirety, or from antibody-displaying phage.

[0279] Recombinant expression in host cells is particularly useful when fragments or derivatives of the antibodies of the present invention are desired.

[0280] Host cells for recombinant production of either whole antibodies, antibody fragments, or antibody derivatives can be prokaryotic or eukaryotic.

[0281] Prokaryotic hosts are particularly useful for producing phage displayed antibodies of the present invention.

[0282] The technology of phage-displayed antibodies, in which antibody variable region fragments are fused, for example, to the gene III protein (plIII) or gene VIII protein (PVIII) for display on the surface of filamentous phage, such as M13, is by now well-established. See, e.g., Sidhu, Curr. Opin. Biotechnol. 11(6): 610-6 (2000); Griffiths et al., Curr. Opin. Biotechnol. 9(1): 102-8 (1998); Hoogenboom et al., Immunotechnology, 4(1): 1-20 (1998); Rader et al., Current Opinion in Biotechnology 8: 503-508 (1997); Aujame et al., Human Antibodies 8: 155-168 (1997); Hoogenboom, Trends in Biotechnol. 15: 62-70 (1997); de Kruif et al., 17: 453-455 (1996); Barbas et al., Trends in Biotechnol. 14: 230-234 (1996); Winter et al., Ann. Rev. Immunol. 433-455 (1994). Techniques and protocols required to generate, propagate, screen (pan), and use the antibody fragments from such libraries have recently been compiled. See, e.g., Barbas (2001), supra; Kay, supra; Abelson, supra, the disclosures of which are incorporated herein by reference in their entireties.

[0283] Typically, phage-displayed antibody fragments are scFv fragments or Fab fragments; when desired, full length antibodies can be produced by cloning the variable regions from the displaying phage into a complete antibody and expressing the full length antibody in a further prokaryotic or a eukaryotic host cell.

[0284] Eukaryotic cells are also useful for expression of the antibodies, antibody fragments, and antibody derivatives of the present invention.

[0285] For example, antibody fragments of the present invention can be produced in Pichia pastoris and in Saccharomyces cerevisiae. See, e.g., Takahashi et al., Biosci. Biotechnol. Biochem. 64(10): 2138-44 (2000); Freyre et al., J. Biotechnol. 76(2-3):1 57-63 (2000); Fischer et al., Biotechnol. Appl. Biochem. 30 (Pt 2): 117-20 (1999); Pennell et al., Res. Immunol. 149(6): 599-603 (1998); Eldin et al., J Immunol. Methods. 201(1): 67-75 (1997);, Frenken et al., Res. Immunol. 149(6): 589-99 (1998); Shusta et al., Nature Biotechnol. 16(8): 773-7 (1998), the disclosures of which are incorporated herein by reference in their entireties.

[0286] Antibodies, including antibody fragments and derivatives, of the present invention can also be produced in insect cells. See, e.g., Li et al., Protein Expr. Purif 21(1): 121-8 (2001); Ailor et al., Biotechnol. Bioeng. 58(2-3): 196-203 (1998); Hsu et al., Biotechnol. Prog. 13(1): 96-104 (1997); Edelman et al., Immunology 91(1): 13-9 (1997); and Nesbit et al., J. Immunol. Methods 151(1-2): 201-8 (1992), the disclosures of which are incorporated herein by reference in their entireties.

[0287] Antibodies and fragments and derivatives thereof of the present invention can also be produced in plant cells, particularly maize or tobacco, Giddings et al., Nature Biotechnol. 18(11): 1151-5 (2000); Gavilondo et al., Biotechniques 29(1): 128-38 (2000); Fischer et al., J. Biol. Regul. Homeost. Agents 14(2): 83-92 (2000); Fischer et al., Biotechnol. Appl. Biochem. 30 (Pt 2): 113-6 (1999); Fischer et al., Biol. Chem. 380(7-8): 825-39 (1999); Russell, Curr. Top. Microbiol. Immunol. 240: 119-38 (1999); and Ma et al., Plant Physiol. 109(2): 341-6 (1995), the disclosures of which are incorporated herein by reference in their entireties.

[0288] Antibodies, including antibody fragments and derivatives, of the present invention can also be produced in transgenic, non-human, mammalian milk. See, e.g. Pollock et al., J. Immunol Methods. 231: 147-57 (1999); Young et al., R.es. Immunol. 149: 609-10 (1998); Limonta et al., Immunotechnology 1: 107-13 (1995), the disclosures of which are incorporated herein by reference in their entireties.

[0289] Mammalian cells useful for recombinant expression of antibodies, antibody fragments, and antibody derivatives of the present invention include CHO cells, COS cells, 293 cells, and myeloma cells.

[0290] Verma et al., J. Immunol. Methods 216(1-2):165-81 (1998), herein incorporated by reference, review and compare bacterial, yeast, insect and mammalian expression systems for expression of antibodies.

[0291] Antibodies of the present invention can also be prepared by cell free translation, as further described in Merk et al., J. Biochem. (Tokyo) 125(2): 328-33 (1999) and Ryabova et al., Nature Biotechnol. 15(1): 79-84 (1997), and in the milk of transgenic animals, as further described in Pollock et al., J. Immunol. Methods 231(1-2): 147-57 (1999), the disclosures of which are incorporated herein by reference in their entireties.

[0292] The invention further provides antibody fragments that bind specifically to one or more of the proteins and protein fragments of the present invention, to one or more of the proteins and protein fragments encoded by the isolated nucleic acids of the present invention, or the binding of which can be competitively inhibited by one or more of the proteins and protein fragments of the present invention or one or more of the proteins and protein fragments encoded by the isolated nucleic acids of the present invention.

[0293] Among such useful fragments are Fab, Fab′, Fv, F(ab)′₂, and single chain Fv (scFv) fragments. Other useful fragments are described in Hudson, Curr. Opin. Biotechnol. 9(4): 395-402 (1998).

[0294] It is also an aspect of the present invention to provide antibody derivatives that bind specifically to one or more of the proteins and protein fragments of the present invention, to one or more of the proteins and protein fragments encoded by the isolated nucleic acids of the present invention, or the binding of which can be competitively inhibited by one or more of the proteins and protein fragments of the present invention or one or more of the proteins and protein fragments encoded by the isolated nucleic acids of the present invention.

[0295] Among such useful derivatives are chimeric, primatized, and humanized antibodies; such derivatives are less immunogenic in human beings, and thus more suitable for in vivo administration, than are unmodified antibodies from non-human mammalian species. Another useful derivative is PEGylation to increase the serum half life of the antibodies.

[0296] Chimeric antibodies typically include heavy and/or light chain variable regions (including both CDR and framework residues) of immunoglobulins of one species, typically mouse, fused to constant regions of another species, typically human. See, e.g., U.S. Pat. No. 5,807,715; Morrison et al., Proc. Natl. Acad. Sci USA.81(21): 6851-5 (1984); Sharon et al., Nature 309(5966): 364-7 (1984); Takeda et al, Nature 314(6010): 452-4 (1985), the disclosures of which are incorporated herein by reference in their entireties. Primatized and humanized antibodies typically include heavy and/or light chain CDRs from a murine antibody grafted into a non-human primate or human antibody V region framework, usually further comprising a human constant region, Riechmann et al, Nature 332(6162): 323-7 (1988); Co et al., Nature 351(6326): 501-2 (1991); U.S. Pat. Nos. 6,054,297; 5,821,337; 5,770,196; 5,766,886; 5,821,123; 5,869,619; 6,180,377; 6,013,256; 5,693,761; and 6,180,370, the disclosures of which are incorporated herein by reference in their entireties.

[0297] Other useful antibody derivatives of the invention include heteromeric antibody complexes and antibody fusions, such as diabodies (bispecific antibodies), single-chain diabodies, and intrabodies.

[0298] It is contemplated that the nucleic acids encoding the antibodies of the present invention can be operably joined to other nucleic acids forming a recombinant vector for cloning or for expression of the antibodies of the invention. The present invention includes any recombinant vector containing the coding sequences, or part thereof, whether for eukaryotic transduction, transfection or gene therapy. Such vectors may be prepared using conventional molecular biology techniques, known to those with skill in the art, and would comprise DNA encoding sequences for the immunoglobulin V-regions including framework and CDRs or parts thereof, and a suitable promoter either with or without a signal sequence for intracellular transport. Such vectors may be transduced or transfected into eukaryotic cells or used for gene therapy (Marasco et al., Proc. Natl. Acad. Sci. (USA) 90: 7889-7893 (1993); Duan et al., Proc. Natl. Acad. Sci. (USA) 91: 5075-5079 (1994), by conventional techniques, known to those with skill in the art.

[0299] The antibodies of the present invention, including fragments and derivatives thereof, can usefully be labeled. It is, therefore, another aspect of the present invention to provide labeled antibodies that bind specifically to one or more of the proteins and protein fragments of the present invention, to one or more of the proteins and protein fragments encoded by the isolated nucleic acids of the present invention, or the binding of which can be competitively inhibited by one or more of the proteins and protein fragments of the present invention or one or more of the proteins and protein fragments encoded by the isolated nucleic acids of the present invention.

[0300] The choice of label depends, in part, upon the desired use.

[0301] For example, when the antibodies of the present invention are used for immunohistochemical staining of tissue samples, the label is preferably an enzyme that catalyzes production and local deposition of a detectable product.

[0302] Enzymes typically conjugated to antibodies to permit their immunohistochemical visualization are well-known, and include alkaline phosphatase, β-galactosidase, glucose oxidase, horseradish peroxidase (HRP), and urease. Typical substrates for production and deposition of visually detectable products include o-nitrophenyl-beta-D-galactopyranoside (ONPG); o-phenylenediamine dihydrochloride (OPD); p-nitrophenyl phosphate (PNPP); p-nitrophenyl-beta-D-galactopryanoside (PNPG); 3′,3′-diaminobenzidine (DAB); 3-amino-9-ethylcarbazole (AEC); 4-chloro-1-naphthol (CN); 5-bromo-4-chloro-3-indolyl-phosphate (13CIP); ABTS®; BluoGal; iodonitrotetrazolium (INT); nitroblue tetrazolium chloride (NBT); phenazine methosulfate (PMS); phenolphthalein monophosphate (PMP); tetramethyl benzidine (TMB); tetranitroblue tetrazolium (TNBT); X-Gal; X-Gluc; and X-Glucoside.

[0303] Other substrates can be used to produce products for local deposition that are luminescent. For example, in the presence of hydrogen peroxide (H₂O₂), horseradish peroxidase (HRP) can catalyze the oxidation of cyclic diacylhydrazides, such as luminol. Immediately following the oxidation, the luminol is in an excited state (intermediate reaction product), which decays to the ground state by emitting light. Strong enhancement of the light emission is produced by enhancers, such as phenolic compounds. Advantages include high sensitivity, high resolution, and rapid detection without radioactivity and requiring only small amounts of antibody. See, e.g., Thorpe et al., Methods Enzymol. 133: 331-53 (1986); Kricka et al., J. Immunoassay 17(1): 67-83 (1996); and Lundqvist et al, J. Biolumin. Chemilumin. 10(6): 353-9 (1995), the disclosures of which are incorporated herein by reference in their entireties. Kits for such enhanced chemiluminescent detection (ECL) are available commercially.

[0304] The antibodies can also be labeled using colloidal gold.

[0305] As another example, when the antibodies of the present invention are used, e.g., for flow cytometric detection, for scanning laser cytometric detection, or for fluorescent immunoassay, they can usefully be labeled with fluorophores.

[0306] There are a wide variety of fluorophore labels that can usefully be attached to the antibodies of the present invention.

[0307] For flow cytometric applications, both for extracellular detection and for intracellular detection, common useful fluorophores can be fluorescein isothiocyanate (FITC), allophycocyanin (APC), R-phycoerythrin (PE), peridinin chlorophyll protein (PerCP), Texas Red, Cy3, Cy5, fluorescence resonance energy tandem fluorophores such as PerCP-Cy5.5, PE-Cy5, PE-Cy5.5, PE-Cy7, PE-Texas Red, and APC-Cy7.

[0308] Other fluorophores include, inter alia, Alexa Fluor® 350, Alexa Fluor® 488, Alexa Fluor® 532, Alexa Fluor® 546, Alexa Fluor® 568, Alexa Fluort 594, Alexa Fluor® 647 (monoclonal antibody labeling kits available from Molecular Probes, Inc., Eugene, Oreg., USA), BODIPY dyes, such as BODIPY 493/503, BODIPY FL, BODIPY R6G, BODIPY 530/550, BODIPY TMR, BODIPY 558/568, BODIPY 558/568, BODIPY 564/570, BODIPY 576/589, BODIPY 581/591, BODIPY TR, BODIPY 630/650, BODIPY 650/665, Cascade Blue, Cascade Yellow, Dansyl, lissamine rhodamine B, Marina Blue, Oregon Green 488, Oregon Green 514, Pacific Blue, rhodamine 6G, rhodamine green, rhodamine red, tetramethylrhodamine, Texas Red (available from Molecular Probes, Inc., Eugene, Oreg., USA), and Cy2, Cy3, Cy3.5, Cy5, Cy5.5, Cy7, all of which are also useful for fluorescently labeling the antibodies of the present invention.

[0309] For secondary detection using labeled avidin, streptavidin, captavidin or neutravidin, the antibodies of the present invention can usefully be labeled with biotin.

[0310] When the antibodies of the present invention are used, e.g., for Western blotting applications, they can usefully be labeled with radioisotopes, such as ³³P, ³²P, 35S, ³H, and ¹²⁵I.

[0311] As another example, when the antibodies of the present invention are used for radioimmunotherapy, the label can usefully be ²²⁸Th, ²²⁷Ac, ²²⁵Ac, ²²³Ra, ²³Bi, ²¹²Pb, ²¹²Bi, ²¹¹At, ²⁰³Pb, ¹⁹⁴OS, ¹⁸⁸Re, ¹⁸⁶Re, ¹⁵³Sm, ¹⁴⁹Tb, ¹³¹I, ¹²⁵I, ¹¹¹In, ¹⁰⁵Rh, ^(99m)Tc, ⁹⁷Ru, ⁹⁰Y, ⁹⁰Sr, ⁸⁸Y, ⁷²Se, ⁶⁷Cu, or ⁴⁷Sc.

[0312] As another example, when the antibodies of the present invention are to be used for in vivo diagnostic use, they can be rendered detectable by conjugation to MRI contrast agents, such as gadolinium diethylenetriaminepentaacetic acid (DTPA), Lauffer et al., Radiology 207(2): 529-38 (1998), or by radioisotopic labeling.

[0313] As would be understood, use of the labels described above is not restricted to the application for which they are mentioned.

[0314] The antibodies of the present invention, including fragments and derivatives thereof, can also be conjugated to toxins, in order to target the toxin's ablative action to cells that display and/or express the proteins of the present invention. Commonly, the antibody in such immunotoxins is conjugated to Pseudomonas exotoxin A, diphtheria toxin, shiga toxin A, anthrax toxin lethal factor, or ricin. See Hall (ed.), Immunotoxin Methods and Protocols (Methods in Molecular Biology, vol. 166), Humana Press (2000); and Frankel et al. (eds.), Clinical Applications of Immunotoxins, Springer-Verlag (1998), the disclosures of which are incorporated herein by reference in their entireties.

[0315] The antibodies of the present invention can usefully be attached to a substrate, and it is, therefore, another aspect of the invention to provide antibodies that bind specifically to one or more of the proteins and protein fragments of the present invention, to one or more of the proteins and protein fragments encoded by the isolated nucleic acids of the present invention, or the binding of which can be competitively inhibited by one or more of the proteins and protein fragments of the present invention or one or more of the proteins and protein fragments encoded by the isolated nucleic acids of the present invention, attached to a substrate.

[0316] Substrates can be porous or nonporous, planar or nonplanar.

[0317] For example, the antibodies of the present invention can usefully be conjugated to filtration media, such as NHS-activated Sepharose or CNBr-activated Sepharose for purposes of immunoaffinity chromatography.

[0318] For example, the antibodies of the present invention can usefully be attached to paramagnetic microspheres, typically by biotin-streptavidin interaction, which microspheres can then be used for isolation of cells that express or display the proteins of the present invention. As another example, the antibodies of the present invention can usefully be attached to the surface of a microtiter plate for ELISA.

[0319] As noted above, the antibodies of the present invention can be produced in prokaryotic and eukaryotic cells. It is, therefore, another aspect of the present invention to provide cells that express the antibodies of the present invention, including hybridoma cells, B cells, plasma cells, and host cells recombinantly modified to express the antibodies of the present invention.

[0320] In yet a further aspect, the present invention provides aptamers evolved to bind specifically to one or more of the proteins and protein fragments of the present invention, to one or more of the proteins and protein fragments encoded by the isolated nucleic acids of the present invention, or the binding of which can be competitively inhibited by one or more of the proteins and protein fragments of the present invention or one or more of the proteins and protein fragments encoded by the isolated nucleic acids of the present invention.

[0321] In sum, one of skill in the art, provided with the teachings of this invention, has available a variety of methods which may be used to alter the biological properties of the antibodies of this invention including methods which would increase or decrease the stability or half-life, immunogenicity, toxicity, affinity or yield of a given antibody molecule, or to alter it in any other way that may render it more suitable for a particular application.

[0322] Transgenic Animals and Cells

[0323] In another aspect, the invention provides transgenic cells and non-human organisms comprising nucleic acid molecules of the invention. In a preferred embodiment, the transgenic cells and non-human organisms comprise a nucleic acid molecule encoding an LSP. In a preferred embodiment, the LSP comprises an amino acid sequence selected from SEQ ID NO: 165 through 284, or a fragment, mutein, homologous protein or allelic variant thereof. In another preferred embodiment, the transgenic cells and non-human organism comprise an LSNA of the invention, preferably an LSNA comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 1 through 164, or a part, substantially similar nucleic acid molecule, allelic variant or hybridizing nucleic acid molecule thereof.

[0324] In another embodiment, the transgenic cells and non-human organisms have a targeted disruption or replacement of the endogenous orthologue of the human LSG. The transgenic cells can be embryonic stem cells or somatic cells. The transgenic non-human organisms can be chimeric, nonchimeric heterozygotes, and nonchimeric homozygotes. Methods of producing transgenic animals are well-known in the art. See, e.g., Hogan et al., Manipulating the Mouse Embryo: A Laboratory Manual, 2d ed., Cold Spring Harbor Press (1999); Jackson et al., Mouse Genetics and Transgenics: A Practical Approach, Oxford University Press (2000); and Pinkert, Transgenic Animal Technology: A Laboratory Handbook, Academic Press (1999).

[0325] Any technique known in the art may be used to introduce a nucleic acid molecule of the invention into an animal to produce the founder lines of transgenic animals. Such techniques include, but are not limited to, pronuclear microinjection. (see, e.g., Paterson et al., Appl. Microbiol Biotechnol. 40: 691-698 (1994); Carver et al., Biotechnology 11: 1263-1270 (1993); Wright et al., Biotechnology 9: 830-834 (1991); and U.S. Pat. No. 4,873,191 (1989 retrovirus-mediated gene transfer into germ lines, blastocysts or embryos (see, e.g., Van der Putten et al., Proc. Natl. Acad. Sci., USA 82: 6148-6152 (1985)); gene targeting in embryonic stem cells (see, e.g., Thompson et al., Cell 56: 313-321 (1989)); electroporation of cells or embryos (see, e.g., Lo, 1983, Mol. Cell. Biol. 3: 1803-1814 (1983)); introduction using a gene gun (see, e.g., Ulmer et al., Science 259: 1745-49 (1993); introducing nucleic acid constructs into embryonic pleuripotent stem cells and transferring the stem cells back into the blastocyst; and sperm-mediated gene transfer (see, e.g., Lavitrano et al., Cell 57: 717-723 (1989)).

[0326] Other techniques include, for example, nuclear transfer into enucleated oocytes of nuclei from cultured embryonic, fetal, or adult cells induced to quiescence (see, e.g., Campell et al., Nature 380: 64-66 (1996); Wilmut et al., Nature 385: 810-813 (1997)). The present invention provides for transgenic animals that carry the transgene (i.e., a nucleic acid molecule of the invention) in all their cells, as well as animals which carry the transgene in some, but not all their cells, i.e., mosaic animals or chimeric animals.

[0327] The transgene may be integrated as a single transgene or as multiple copies, such as in concatamers, e.g., head-to-head tandems or head-to-tail tandems. The transgene may also be selectively introduced into and activated in a particular cell type by following, e.g., the teaching of Lasko et al. et al., Proc. Natl. Acad. Sci. USA 89: 6232-6236 (1992). The regulatory sequences required for such a cell-type specific activation will depend upon the particular cell type of interest, and will be apparent to those of skill in the art.

[0328] Once transgenic animals have been generated, the expression of the recombinant gene may be assayed utilizing standard techniques. Initial screening may be accomplished by Southern blot analysis or PCR techniques to analyze animal tissues to verify that integration of the transgene has taken place. The level of mRNA expression of the transgene in the tissues of the transgenic animals may also be assessed using techniques which include, but are not limited to, Northern blot analysis of tissue samples obtained from the animal, in situ hybridization analysis, and reverse transcriptase-PCR (RT-PCR). Samples of transgenic gene-expressing tissue may also be evaluated immunocytochemically or immunohistochemically using antibodies specific for the transgene product.

[0329] Once the founder animals are produced, they may be bred, inbred, outbred, or crossbred to produce colonies of the particular animal. Examples of such breeding strategies include, but are not limited to: outbreeding of founder animals with more than one integration site in order to establish separate lines; inbreeding of separate lines in order to produce compound transgenics that express the transgene at higher levels because of the effects of additive expression of each transgene; crossing of heterozygous transgenic animals to produce animals homozygous for a given integration site in order to both augment expression and eliminate the need for screening of animals by DNA analysis; crossing of separate homozygous lines to produce compound heterozygous or homozygous lines; and breeding to place the transgene on a distinct background that is appropriate for an experimental model of interest.

[0330] Transgenic animals of the invention have uses which include, but are not limited to, animal model systems useful in elaborating the biological flnction of polypeptides of the present invention, studying conditions and/or disorders associated with aberrant expression, and in screening for compounds effective in ameliorating such conditions and/or disorders.

[0331] Methods for creating a transgenic animal with a disruption of a targeted gene are also well-known in the art. In general, a vector is designed to comprise some nucleotide sequences homologous to the endogenous targeted gene. The vector is introduced into a cell so that it may integrate, via homologous recombination with chromosomal sequences, into the endogenous gene, thereby disrupting the function of the endogenous gene. The transgene may also be selectively introduced into a particular cell type, thus inactivating the endogenous gene in only that cell type. See, e.g., Gu et al., Science 265: 103-106 (1994). The regulatory sequences required for such a cell-type specific inactivation will depend upon the particular cell type of interest, and will be apparent to those of skill in the art. See, e.g., Smithies et al., Nature 317: 230-234 (1985); Thomas et al, Cell 51: 503-512 (1987); Thompson et al., Cell 5: 313-321 (1989).

[0332] In one embodiment, a mutant, non-functional nucleic acid molecule of the invention (or a completely unrelated DNA sequence) flanked by DNA homologous to the endogenous nucleic acid sequence (either the coding regions or regulatory regions of the gene) can be used, with or without a selectable marker and/or a negative selectable marker, to transfect cells that express polypeptides of the invention in vivo. In another embodiment, techniques known in the art are used to generate knockouts in cells that contain, but do not express the gene of interest. Insertion of the DNA construct, via targeted homologous recombination, results in inactivation of the targeted gene. Such approaches are particularly suited in research and agricultural fields where modifications to embryonic stem cells can be used to generate animal offspring with an inactive targeted gene. See, e.g., Thomas, supra and Thompson, supra. However this approach can be routinely adapted for use in humans provided the recombinant DNA constructs are directly administered or targeted to the required site in vivo using appropriate viral vectors that will be apparent to those of skill in the art.

[0333] In further embodiments of the invention, cells that are genetically engineered to express the polypeptides of the invention, or alternatively, that are genetically engineered not to express the polypeptides of the invention (e.g., knockouts) are administered to a patient in vivo. Such cells may be obtained from an animal or patient or an MHC compatible donor and can include, but are not limited to fibroblasts, bone marrow cells, blood cells (e.g., lymphocytes), adipocytes, muscle cells, endothelial cells etc. The cells are genetically engineered in vitro using recombinant DNA techniques to introduce the coding sequence of polypeptides of the invention into the cells, or alternatively, to disrupt the coding sequence and/or endogenous regulatory sequence associated with the polypeptides of the invention, e.g., by transduction (using viral vectors, and preferably vectors that integrate the transgene into the cell genome) or transfection procedures, including, but not limited to, the use of plasmids, cosmids, YACs, naked DNA, electroporation, liposomes, etc.

[0334] The coding sequence of the polypeptides of the invention can be placed under the control of a strong constitutive or inducible promoter or promoter/enhancer to achieve expression, and preferably secretion, of the polypeptides of the invention. The engineered cells which express and preferably secrete the polypeptides of the invention can be introduced into the patient systemically, e.g., in the circulation, or intraperitoneally.

[0335] Alternatively, the cells can be incorporated into a matrix and implanted in the body, e.g., genetically engineered fibroblasts can be implanted as part of a skin graft; genetically engineered endothelial cells can be implanted as part of a lymphatic or vascular graft. See, e.g., U.S. Pat. Nos. 5,399,349 and 5,460,959, each of which is incorporated by reference herein in its entirety.

[0336] When the cells to be administered are non-autologous or non-MHC compatible cells, they can be administered using well-known techniques which prevent the development of a host immune response against the introduced cells. For example, the cells may be introduced in an encapsulated form which, while allowing for an exchange of components with the immediate extracellular environment, does not allow the introduced cells to be recognized by the host immune system.

[0337] Transgenic and “knock-out” animals of the invention have uses which include, but are not limited to, animal model systems useful in elaborating the biological function of polypeptides of the present invention, studying conditions and/or disorders associated with aberrant expression, and in screening for compounds effective in ameliorating such conditions and/or disorders.

[0338] Computer Readable Means

[0339] A further aspect of the invention relates to a computer readable means for storing the nucleic acid and amino acid sequences of the instant invention. In a preferred embodiment, the invention provides a computer readable means for storing SEQ ID NO: 1 through 164 and SEQ ID NO: 165 through 284 as described herein, as the complete set of sequences or in any combination. The records of the computer readable means can be accessed for reading and display and for interface with a computer system for the application of programs allowing for the location of data upon a query for data meeting certain criteria, the comparison of sequences, the alignment or ordering of sequences meeting a set of criteria, and the like.

[0340] The nucleic acid and amino acid sequences of the invention are particularly useful as components in databases useful for search analyses as well as in sequence analysis algorithms. As used herein, the terms “nucleic acid sequences of the invention” and “amino acid sequences of the invention” mean any detectable chemical or physical characteristic of a polynucleotide or polypeptide of the invention that is or may be reduced to or stored in a computer readable form. These include, without limitation, chromatographic scan data or peak data, photographic data or scan data therefrom, and mass spectrographic data.

[0341] This invention provides computer readable media having stored thereon sequences of the invention. A computer readable medium may comprise one or more of the following: a nucleic acid sequence comprising a sequence of a nucleic acid sequence of the invention; an amino acid sequence comprising an amino acid sequence of the invention; a set of nucleic acid sequences wherein at least one of said sequences comprises the sequence of a nucleic acid sequence of the invention; a set of amino acid sequences wherein at least one of said sequences comprises the sequence of an amino acid sequence of the invention; a data set representing a nucleic acid sequence comprising the sequence of one or more nucleic acid sequences of the invention; a data set representing a nucleic acid sequence encoding an amino acid sequence comprising the sequence of an amino acid sequence of the invention; a set of nucleic acid sequences wherein at least one of said sequences comprises the sequence of a nucleic acid sequence of the invention; a set of amino acid sequences wherein at least one of said sequences comprises the sequence of an amino acid sequence of the invention; a data set representing a nucleic acid sequence comprising the sequence of a nucleic acid sequence of the invention; a data set representing a nucleic acid sequence encoding an amino acid sequence comprising the sequence of an amino acid sequence of the invention. The computer readable medium can be any composition of matter used to store information or data, including, for example, commercially available floppy disks, tapes, hard drives, compact disks, and video disks.

[0342] Also provided by the invention are methods for the analysis of character sequences, particularly genetic sequences. Preferred methods of sequence analysis include, for example, methods of sequence homology analysis, such as identity and similarity analysis, RNA structure analysis, sequence assembly, cladistic analysis, sequence motif analysis, open reading frame determination, nucleic acid base calling, and sequencing chromatogram peak analysis.

[0343] A computer-based method is provided for performing nucleic acid sequence identity or similarity identification. This method comprises the steps of providing a nucleic acid sequence comprising the sequence of a nucleic acid of the invention in a computer readable medium; and comparing said nucleic acid sequence to at least one nucleic acid or amino acid sequence to identify sequence identity or similarity.

[0344] A computer-based method is also provided for performing amino acid homology identification, said method comprising the steps of: providing an amino acid sequence comprising the sequence of an amino acid of the invention in a computer readable medium; and comparing said an amino acid sequence to at least one nucleic acid or an amino acid sequence to identify homology.

[0345] A computer-based method is still further provided for assembly of overlapping nucleic acid sequences into a single nucleic acid sequence, said method comprising the steps of: providing a first nucleic acid sequence comprising the sequence of a nucleic acid of the invention in a computer readable medium; and screening for at least one overlapping region between said first nucleic acid sequence and a second nucleic acid sequence.

[0346] Diagnostic Methods for Lung Cancer

[0347] The present invention also relates to quantitative and qualitative diagnostic assays and methods for detecting, diagnosing, monitoring, staging and predicting cancers by comparing expression of an LSNA or an LSP in a human patient that has or may have lung cancer, or who is at risk of developing lung cancer, with the expression of an LSNA or an LSP in a normal human control. For purposes of the present invention, “expression of an LSNA” or “LSNA expression” means the quantity of LSG mRNA that can be measured by any method known in the art or the level of transcription that can be measured by any method known in the art in a cell, tissue, organ or whole patient. Similarly, the term “expression of an LSP” or “LSP expression” means the amount of LSP that can be measured by any method known in the art or the level of translation of an LSG LSNA that can be measured by any method known in the art.

[0348] The present invention provides methods for diagnosing lung cancer in a patient, in particular squamous cell carcinoma, by analyzing for changes in levels of LSNA or LSP in cells, tissues, organs or bodily fluids compared with levels of LSNA or LSP in cells, tissues, organs or bodily fluids of preferably the same type from a normal human control, wherein an increase, or decrease in certain cases, in levels of an LSNA or LSP in the patient versus the normal human control is associated with the presence of lung cancer or with a predilection to the disease. In another preferred embodiment, the present invention provides methods for diagnosing lung cancer in a patient by analyzing changes in the structure of the mRNA of an LSG compared to the mRNA from a normal control. These changes include, without limitation, aberrant splicing, alterations in polyadenylation and/or alterations in 5′ nucleotide capping. In yet another preferred embodiment, the present invention provides methods for diagnosing lung cancer in a patient by analyzing changes in an LSP compared to an LSP from a normal control. These changes include, e.g., alterations in glycosylation and/or phosphorylation of the LSP or subcellular LSP localization.

[0349] In a preferred embodiment, the expression of an LSNA is measured by determining the amount of an mRNA that encodes an amino acid sequence selected from SEQ ID NO: 165 through 284, a homolog, an allelic variant, or a fragment thereof. In a more preferred embodiment, the LSNA expression that is measured is the level of expression of an LSNA mRNA selected from SEQ ID NO: 1 through 164, or a hybridizing nucleic acid, homologous nucleic acid or allelic variant thereof, or a part of any of these nucleic acids. LSNA expression may be measured by any method known in the art, such as those described supra, including measuring mRNA expression by Northern blot, quantitative or qualitative reverse transcriptase PCR (RT-PCR), microarray, dot or slot blots or in situ hybridization. See, e.g., Ausubel (1992), supra; Ausubel (1999), supra; Sambrook (1989), supra; and Sambrook (2001), supra. LSNA transcription may be measured by any method known in the art including using a reporter gene hooked up to the promoter of an LSG of interest or doing nuclear run-off assays. Alterations in mRNA structure, e.g., aberrant splicing variants, may be determined by any method known in the art, including, RT-PCR followed by sequencing or restriction analysis. As necessary, LSNA expression may be compared to a known control, such as normal lung nucleic acid, to detect a change in expression.

[0350] In another preferred embodiment, the expression of an LSP is measured by determining the level of an LSP having an amino acid sequence selected from the group consisting of SEQ ID NO: 165 through 284, a homolog, an allelic variant, or a fragment thereof. Such levels are preferably determined in at least one of cells, tissues, organs and/or bodily fluids, including determination of normal and abnormal levels. Thus, for instance, a diagnostic assay in accordance with the invention for diagnosing over- or underexpression of LSNA or LSP compared to normal control bodily fluids, cells, or tissue samples may be used to diagnose the presence of lung cancer. The expression level of an LSP may be determined by any method known in the art, such as those described supra. In a preferred embodiment, the LSP expression level may be determined by radioimmunoassays, competitive-binding assays, ELISA, Western blot, FACS, immunohistochemistry, immunoprecipitation, proteomic approaches: two-dimensional gel electrophoresis (2D electrophoresis) and non-gel-based approaches such as mass spectrometry or protein interaction profiling. See, e.g, Harlow (1999), supra; Ausubel (1992), supra; and Ausubel (1999), supra. Alterations in the LSP structure may be determined by any method known in the art, including, e.g., using antibodies that specifically recognize phosphoserine, phosphothreonine or phosphotyrosine residues, two-dimensional polyacrylamide gel electrophoresis (2D PAGE) and/or chemical analysis of amino acid residues of the protein. Id.

[0351] In a preferred embodiment, a radioimmunoassay (RIA) or an ELISA is used. An antibody specific to an LSP is prepared if one is not already available. In a preferred embodiment, the antibody is a monoclonal antibody. The anti-LSP antibody is bound to a solid support and any free protein binding sites on the solid support are blocked with a protein such as bovine serum albumin. A sample of interest is incubated with the antibody on the solid support under conditions in which the LSP will bind to the anti-LSP antibody. The sample is removed, the solid support is washed to remove unbound material, and an anti-LSP antibody that is linked to a detectable reagent (a radioactive substance for RIA and an enzyme for ELISA) is added to the solid support and incubated under conditions in which binding of the LSP to the labeled antibody will occur. After binding, the unbound labeled antibody is removed by washing. For an ELISA, one or more substrates are added to produce a colored reaction product that is based upon the amount of an LSP in the sample. For an RIA, the solid support is counted for radioactive decay signals by any method known in the art. Quantitative results for both RIA and ELISA typically are obtained by reference to a standard curve.

[0352] Other methods to measure LSP levels are known in the art. For instance, a competition assay may be employed wherein an anti-LSP antibody is attached to a solid support and an allocated amount of a labeled LSP and a sample of interest are incubated with the solid support. The amount of labeled LSP detected which is attached to the solid support can be correlated to the quantity of an LSP in the sample.

[0353] Of the proteomic approaches, 2D PAGE is a well-known technique. Isolation of individual proteins from a sample such as serum is accomplished using sequential separation of proteins by isoelectric point and molecular weight. Typically, polypeptides are first separated by isoelectric point (the first dimension) and then separated by size using an electric current (the second dimension). In general, the second dimension is perpendicular to the first dimension. Because no two proteins with different sequences are identical on the basis of both size and charge, the result of 2D PAGE is a roughly square gel in which each protein occupies a unique spot. Analysis of the spots with chemical or antibody probes, or subsequent protein microsequencing can reveal the relative abundance of a given protein and the identity of the proteins in the sample.

[0354] Expression levels of an LSNA can be determined by any method known in the art, including PCR and other nucleic acid methods, such as ligase chain reaction (LCR) and nucleic acid sequence based amplification (NASBA), can be used to detect malignant cells for diagnosis and monitoring of various malignancies. For example, reverse-transcriptase PCR (RT-PCR) is a powerful technique which can be used to detect the presence of a specific mRNA population in a complex mixture of thousands of other mRNA species. In RT-PCR, an mRNA species is first reverse transcribed to complementary DNA (cDNA) with use of the enzyme reverse transcriptase; the cDNA is then amplified as in a standard PCR reaction.

[0355] Hybridization to specific DNA molecules (e.g., oligonucleotides) arrayed on a solid support can be used to both detect the expression of and quantitate the level of expression of one or more LSNAs of interest. In this approach, all or a portion of one or more LSNAs is fixed to a substrate. A sample of interest, which may comprise RNA, e.g., total RNA or polyA-selected mRNA, or a complementary DNA (cDNA) copy of the RNA is incubated with the solid support under conditions in which hybridization will occur between the DNA on the solid support and the nucleic acid molecules in the sample of interest. Hybridization between the substrate-bound DNA and the nucleic acid molecules in the sample can be detected and quantitated by several means, including, without limitation, radioactive labeling or fluorescent labeling of the nucleic acid molecule or a secondary molecule designed to detect the hybrid.

[0356] The above tests can be carried out on samples derived from a variety of cells, bodily fluids and/or tissue extracts such as homogenates or solubilized tissue obtained from a patient. Tissue extracts are obtained routinely from tissue biopsy and autopsy material. Bodily fluids useful in the present invention include blood, urine, saliva or any other bodily secretion or derivative thereof. By blood it is meant to include whole blood, plasma, serum or any derivative of blood. In a preferred embodiment, the specimen tested for expression of LSNA or LSP includes, without limitation, lung tissue, fluid obtained by bronchial alveolar lavage (BAL), sputum, lung cells grown in cell culture, blood, serum, lymph node tissue and lymphatic fluid. In another preferred embodiment, especially when metastasis of a primary lung cancer is known or suspected, specimens include, without limitation, tissues from brain, bone, bone marrow, liver, adrenal glands and colon. In general, the tissues may be sampled by biopsy, including, without limitation, needle biopsy, e.g., transthoracic needle aspiration, cervical mediatinoscopy, endoscopic lymph node biopsy, video-assisted thoracoscopy, exploratory thoracotomy, bone marrow biopsy and bone marrow aspiration. See Scott, supra and Franklin, pp. 529-570, in Kane, supra. For early and inexpensive detection, assaying for changes in LSNAs or LSPs in cells in sputum samples may be particularly useful. Methods of obtaining and analyzing sputum samples is disclosed in Franklin, supra.

[0357] All the methods of the present invention may optionally include determining the expression levels of one or more other cancer markers in addition to determining the expression level of an LSNA or LSP. In many cases, the use of another cancer marker will decrease the likelihood of false positives or false negatives. In one embodiment, the one or more other cancer markers include other LSNA or LSPs as disclosed herein. Other cancer markers useful in the present invention will depend on the cancer being tested and are known to those of skill in the art. In a preferred embodiment, at least one other cancer marker in addition to a particular LSNA or LSP is measured. In a more preferred embodiment, at least two other additional cancer markers are used. In an even more preferred embodiment, at least three, more preferably at least five, even more preferably at least ten additional cancer markers are used.

[0358] Diagnosing

[0359] In one aspect, the invention provides a method for determining the expression levels and/or structural alterations of one or more LSNAs and/or LSPs in a sample from a patient suspected of having lung cancer. In general, the method comprises the steps of obtaining the sample from the patient, determining the expression level or structural alterations of an LSNA and/or LSP and then ascertaining whether the patient has lung cancer from the expression level of the LSNA or LSP. In general, if high expression relative to a control of an LSNA or LSP is indicative of lung cancer, a diagnostic assay is considered positive if the level of expression of the LSNA or LSP is at least two times higher, and more preferably are at least five times higher, even more preferably at least ten times higher, than in preferably the same cells, tissues or bodily fluid of a normal human control. In contrast, if low expression relative to a control of an LSNA or LSP is indicative of lung cancer, a diagnostic assay is considered positive if the level of expression of the LSNA or LSP is at least two times lower, more preferably are at least five times lower, even more preferably at least ten times lower than in preferably the same cells, tissues or bodily fluid of a normal human control. The normal human control may be from a different patient or from uninvolved tissue of the same patient.

[0360] The present invention also provides a method of determining whether lung cancer has metastasized in a patient. One may identify whether the lung cancer has metastasized by measuring the expression levels and/or structural alterations of one or more LSNAs and/or LSPs in a variety of tissues. The presence of an LSNA or LSP in a certain tissue at levels higher than that of corresponding noncancerous tissue (e.g., the same tissue from another individual) is indicative of metastasis if high level expression of an LSNA or LSP is associated with lung cancer. Similarly, the presence of an LSNA or LSP in a tissue at levels lower than that of corresponding noncancerous tissue is indicative of metastasis if low level expression of an LSNA or LSP is associated with lung cancer. Further, the presence of a structurally altered LSNA or LSP that is associated with lung cancer is also indicative of metastasis.

[0361] In general, if high expression relative to a control of an LSNA or LSP is indicative of metastasis, an assay for metastasis is considered positive if the level of expression of the LSNA or LSP is at least two times higher, and more preferably are at least five times higher, even more preferably at least ten times higher, than in preferably the same cells, tissues or bodily fluid of a normal human control. In contrast, if low expression relative to a control of an LSNA or LSP is indicative of metastasis, an assay for metastasis is considered positive if the level of expression of the LSNA or LSP is at least two times lower, more preferably are at least five times lower, even more preferably at least ten times lower than in preferably the same cells, tissues or bodily fluid of a normal human control.

[0362] The LSNA or LSP of this invention may be used as element in an array or a multi-analyte test to recognize expression patterns associated with lung cancers or other lung related disorders. In addition, the sequences of either the nucleic acids or proteins may be used as elements in a computer program for pattern recognition of lung disorders.

[0363] Staging

[0364] The invention also provides a method of staging lung cancer in a human patient. The method comprises identifying a human patient having lung cancer and analyzing cells, tissues or bodily fluids from such human patient for expression levels and/or structural alterations of one or more LSNAs or LSPs. First, one or more tumors from a variety of patients are staged according to procedures well-known in the art, and the expression level of one or more LSNAs or LSPs is determined for each stage to obtain a standard expression level for each LSNA and LSP. Then, the LSNA or LSP expression levels are determined in a biological sample from a patient whose stage of cancer is not known. The LSNA or LSP expression levels from the patient are then compared to the standard expression level. By comparing the expression level of the LSNAs and LSPs from the patient to the standard expression levels, one may determine the stage of the tumor. The same procedure may be followed using structural alterations of an LSNA or LSP to determine the stage of a lung cancer.

[0365] Monitoring

[0366] Further provided is a method of monitoring lung cancer in a human patient. One may monitor a human patient to determine whether there has been metastasis and, if there has been, when metastasis began to occur. One may also monitor a human patient to determine whether a preneoplastic lesion has become cancerous. One may also monitor a human patient to determine whether a therapy, e.g., chemotherapy, radiotherapy or surgery, has decreased or eliminated the lung cancer. The method comprises identifying a human patient that one wants to monitor for lung cancer, periodically analyzing cells, tissues or bodily fluids from such human patient for expression levels of one or more LSNAs or LSPs, and comparing the LSNA or LSP levels over time to those LSNA or LSP expression levels obtained previously. Patients may also be monitored by measuring one or more structural alterations in an LSNA or LSP that are associated with lung cancer.

[0367] If increased expression of an LSNA or LSP is associated with metastasis, treatment failure, or conversion of a preneoplastic lesion to a cancerous lesion, then detecting an increase in the expression level of an LSNA or LSP indicates that the tumor is metastasizing, that treatment has failed or that the lesion is cancerous, respectively. One having ordinary skill in the art would recognize that if this were the case, then a decreased expression level would be indicative of no metastasis, effective therapy or failure to progress to a neoplastic lesion. If decreased expression of an LSNA or LSP is associated with metastasis, treatment failure, or conversion of a preneoplastic lesion to a cancerous lesion, then detecting an decrease in the expression level of an LSNA or LSP indicates that the tumor is metastasizing, that treatment has failed or that the lesion is cancerous, respectively. In a preferred embodiment, the levels of LSNAs or LSPs are determined from the same cell type, tissue or bodily fluid as prior patient samples. Monitoring a patient for onset of lung cancer metastasis is periodic and preferably is done on a quarterly basis, but may be done more or less frequently.

[0368] The methods described herein can further be utilized as prognostic assays to identify subjects having or at risk of developing a disease or disorder associated with increased or decreased expression levels of an LSNA and/or LSP. The present invention provides a method in which a test sample is obtained from a human patient and one or more LSNAs and/or LSPs are detected. The presence of higher (or lower) LSNA or LSP levels as compared to normal human controls is diagnostic for the human patient being at risk for developing cancer, particularly lung cancer. The effectiveness of therapeutic agents to decrease (or increase) expression or activity of one or more LSNAs and/or LSPs of the invention can also be monitored by analyzing levels of expression of the LSNAs and/or LSPs in a human patient in clinical trials or in in vitro screening assays such as in human cells. In this way, the gene expression pattern can serve as a marker, indicative of the physiological response of the human patient or cells, as the case maybe, to the agent being tested.

[0369] Detection of Genetic Lesions or Mutations

[0370] The methods of the present invention can also be used to detect genetic lesions or mutations in an LSG, thereby determining if a human with the genetic lesion is susceptible to developing lung cancer or to determine what genetic lesions are responsible, or are partly responsible, for a person's existing lung cancer. Genetic lesions can be detected, for example, by ascertaining the existence of a deletion, insertion and/or substitution of one or more nucleotides from the LSGs of this invention, a chromosomal rearrangement of LSG, an aberrant modification of LSG (such as of the methylation pattern of the genomic DNA), or allelic loss of an LSG. Methods to detect such lesions in the LSG of this invention are known to those having ordinary skill in the art following the teachings of the specification.

[0371] Methods of Detecting Noncancerous Lung Diseases

[0372] The invention also provides a method for determining the expression levels and/or structural alterations of one or more LSNAs and/or LSPs in a sample from a patient suspected of having or known to have a noncancerous lung disease. In general, the method comprises the steps of obtaining a sample from the patient, determining the expression level or structural alterations of an LSNA and/or LSP, comparing the expression level or structural alteration of the LSNA or LSP to a normal lung control, and then ascertaining whether the patient has a noncancerous lung disease. In general, if high expression relative to a control of an LSNA or LSP is indicative of a particular noncancerous lung disease, a diagnostic assay is considered positive if the level of expression of the LSNA or LSP is at least two times higher, and more preferably are at least five times higher, even more preferably at least ten times higher, than in preferably the same cells, tissues or bodily fluid of a normal human control. In contrast, if low expression relative to a control of an LSNA or LSP is indicative of a noncancerous lung disease, a diagnostic assay is considered positive if the level of expression of the LSNA or LSP is at least two times lower, more preferably are at least five times lower, even more preferably at least ten times lower than in preferably the same cells, tissues or bodily fluid of a normal human control. The normal human control may be from a different patient or from uninvolved tissue of the same patient.

[0373] One having ordinary skill in the art may determine whether an LSNA and/or LSP is associated with a particular noncancerous lung disease by obtaining lung tissue from a patient having a noncancerous lung disease of interest and determining which LSNAs and/or LSPs are expressed in the tissue at either a higher or a lower level than in normal lung tissue. In another embodiment, one may determine whether an LSNA or LSP exhibits structural alterations in a particular noncancerous lung disease state by obtaining lung tissue from a patient having a noncancerous lung disease of interest and determining the structural alterations in one or more LSNAs and/or LSPs relative to normal lung tissue.

[0374] Methods for Identifying Lung Tissue

[0375] In another aspect, the invention provides methods for identifying lung tissue. These methods are particularly useful in, e.g., forensic science, lung cell differentiation and development, and in tissue engineering.

[0376] In one embodiment, the invention provides a method for determining whether a sample is lung tissue or has lung tissue-like characteristics. The method comprises the steps of providing a sample suspected of comprising lung tissue or having lung tissue-like characteristics, determining whether the sample expresses one or more LSNAs and/or LSPs, and, if the sample expresses one or more LSNAs and/or LSPs, concluding that the sample comprises lung tissue. In a preferred embodiment, the LSNA encodes a polypeptide having an amino acid sequence selected from SEQ ID NO: 165 through 284, or a homolog, allelic variant or fragment thereof. In a more preferred embodiment, the LSNA has a nucleotide sequence selected from SEQ ID NO: 1 through 164, or a hybridizing nucleic acid, an allelic variant or a part thereof. Determining whether a sample expresses an LSNA can be accomplished by any method known in the art. Preferred methods include hybridization to microarrays, Northern blot hybridization, and quantitative or qualitative RT-PCR. In another preferred embodiment, the method can be practiced by determining whether an LSP is expressed. Determining whether a sample expresses an LSP can be accomplished by any method known in the art. Preferred methods include Western blot, ELISA, RIA and 2D PAGE. In one embodiment, the LSP has an amino acid sequence selected from SEQ ID NO: 165 through 284, or a homolog, allelic variant or fragment thereof. In another preferred embodiment, the expression of at least two LSNAs and/or LSPs is determined. In a more preferred embodiment, the expression of at least three, more preferably four and even more preferably five LSNAs and/or LSPs are determined.

[0377] In one embodiment, the method can be used to determine whether an unknown tissue is lung tissue. This is particularly useful in forensic science, in which small, damaged pieces of tissues that are not identifiable by microscopic or other means are recovered from a crime or accident scene. In another embodiment, the method can be used to determine whether a tissue is differentiating or developing into lung tissue. This is important in monitoring the effects of the addition of various agents to cell or tissue culture, e.g., in producing new lung tissue by tissue engineering. These agents include, e.g., growth and differentiation factors, extracellular matrix proteins and culture medium. Other factors that may be measured for effects on tissue development and differentiation include gene transfer into the cells or tissues, alterations in pH, aqueous:air interface and various other culture conditions.

[0378] Methods for Producing and Modifying Lung Tissue

[0379] In another aspect, the invention provides methods for producing engineered lung tissue or cells. In one embodiment, the method comprises the steps of providing cells, introducing an LSNA or an LSG into the cells, and growing the cells under conditions in which they exhibit one or more properties of lung tissue cells. In a preferred embodiment, the cells are pluripotent. As is well-known in the art, normal lung tissue comprises a large number of different cell types. Thus, in one embodiment, the engineered lung tissue or cells comprises one of these cell types. In another embodiment, the engineered lung tissue or cells comprises more than one lung cell type. Further, the culture conditions of the cells or tissue may require manipulation in order to achieve full differentiation and development of the lung cell tissue. Methods for manipulating culture conditions are well-known in the art.

[0380] Nucleic acid molecules encoding one or more LSPs are introduced into cells, preferably pluripotent cells. In a preferred embodiment, the nucleic acid molecules encode LSPs having amino acid sequences selected from SEQ ID NO: 165 through 284, or homologous proteins, analogs, allelic variants or fragments thereof. In a more preferred embodiment, the nucleic acid molecules have a nucleotide sequence selected from SEQ ID NO: 1 through 164, or hybridizing nucleic acids, allelic variants or parts thereof. In another highly preferred embodiment, an LSG is introduced into the cells. Expression vectors and methods of introducing nucleic acid molecules into cells are well-known in the art and are described in detail, supra.

[0381] Artificial lung tissue may be used to treat patients who have lost some or all of their lung function.

[0382] Pharmaceutical Compositions

[0383] In another aspect, the invention provides pharmaceutical compositions comprising the nucleic acid molecules, polypeptides, antibodies, antibody derivatives, antibody fragments, agonists, antagonists, and inhibitors of the present invention. In a preferred embodiment, the pharmaceutical composition comprises an LSNA or part thereof. In a more preferred embodiment, the LSNA has a nucleotide sequence selected from the group consisting of SEQ ID NO: 1 through 164, a nucleic acid that hybridizes thereto, an allelic variant thereof, or a nucleic acid that has substantial sequence identity thereto. In another preferred embodiment, the pharmaceutical composition comprises an LSP or fragment thereof. In a more preferred embodiment, the LSP having an amino acid sequence that is selected from the group consisting of SEQ ID NO: 165 through 284, a polypeptide that is homologous thereto, a fusion protein comprising all or a portion of the polypeptide, or an analog or derivative thereof. In another preferred embodiment, the pharmaceutical composition comprises an anti-LSP antibody, preferably an antibody that specifically binds to an LSP having an amino acid that is selected from the group consisting of SEQ ID NO: 165 through 284, or an antibody that binds to a polypeptide that is homologous thereto, a fusion protein comprising all or a portion of the polypeptide, or an analog or derivative thereof.

[0384] Such a composition typically contains from about 0.1 to 90% by weight of a therapeutic agent of the invention formulated in and/or with a pharmaceutically acceptable carrier or excipient.

[0385] Pharmaceutical formulation is a well-established art, and is further described in Gennaro (ed.), Remington: The Science and Practice of Pharmacy, 20^(th) ed., Lippincott, Williams & Wilkins (2000); Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7^(th) ed., Lippincott Williams & Wilkins (1999); and Kibbe (ed.), Handbook of Pharmaceutical Excipients American Pharmaceutical Association, 3^(rd) ed. (2000), the disclosures of which are incorporated herein by reference in their entireties, and thus need not be described in detail herein.

[0386] Briefly, formulation of the pharmaceutical compositions of the present invention will depend upon the route chosen for administration. The pharmaceutical compositions utilized in this invention can be administered by various routes including both enteral and parenteral routes, including oral, intravenous, intramuscular, subcutaneous, inhalation, topical, sublingual, rectal, intra-arterial, intramedullary, intrathecal, intraventricular, transmucosal, transdermal, intranasal, intraperitoneal, intrapulmonary, and intrauterine.

[0387] Oral dosage forms can be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for ingestion by the patient.

[0388] Solid formulations of the compositions for oral administration can contain suitable carriers or excipients, such as carbohydrate or protein fillers, such as sugars, including lactose, sucrose, mannitol, or sorbitol; starch from corn, wheat, rice, potato, or other plants; cellulose, such as methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, or microcrystalline cellulose; gums including arabic and tragacanth; proteins such as gelatin and collagen; inorganics, such as kaolin, calcium carbonate, dicalcium phosphate, sodium chloride; and other agents such as acacia and alginic acid.

[0389] Agents that facilitate disintegration and/or solubilization can be added, such as the cross-linked polyvinyl pyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate, microcrystalline cellulose, corn starch, sodium starch glycolate, and alginic acid.

[0390] Tablet binders that can be used include acacia, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone (Povidone™), hydroxypropyl methylcellulose, sucrose, starch and ethylcellulose.

[0391] Lubricants that can be used include magnesium stearates, stearic acid, silicone fluid, talc, waxes, oils, and colloidal silica.

[0392] Fillers, agents that facilitate disintegration and/or solubilization, tablet binders and lubricants, including the aforementioned, can be used singly or in combination.

[0393] Solid oral dosage forms need not be uniform throughout. For example, dragee cores can be used in conjunction with suitable coatings, such as concentrated sugar solutions, which can also contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.

[0394] Oral dosage forms of the present invention include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a coating, such as glycerol or sorbitol. Push-fit capsules can contain active ingredients mixed with a filler or binders, such as lactose or starches, lubricants, such as talc or magnesium stearate, and, optionally, stabilizers. In soft capsules, the active compounds can be dissolved or suspended in suitable liquids, such as fatty oils, liquid, or liquid polyethylene glycol with or without stabilizers.

[0395] Additionally, dyestuffs or pigments can be added to the tablets or dragee coatings for product identification or to characterize the quantity of active compound, i.e., dosage.

[0396] Liquid formulations of the pharmaceutical compositions for oral (enteral) administration are prepared in water or other aqueous vehicles and can contain various suspending agents such as methylcellulose, alginates, tragacanth, pectin, kelgin, carrageenan, acacia, polyvinylpyrrolidone, and polyvinyl alcohol. The liquid formulations can also include solutions, emulsions, syrups and elixirs containing, together with the active compound(s), wetting agents, sweeteners, and coloring and flavoring agents.

[0397] The pharmaceutical compositions of the present invention can also be formulated for parenteral administration. Formulations for parenteral administration can be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions.

[0398] For intravenous injection, water soluble versions of the compounds of the present invention are formulated in, or if provided as a lyophilate, mixed with, a physiologically acceptable fluid vehicle, such as 5% dextrose (“D5”), physiologically buffered saline, 0.9% saline, Hanks' solution, or Ringer's solution. Intravenous formulations may include carriers, excipients or stabilizers including, without limitation, calcium, human serum albumin, citrate, acetate, calcium chloride, carbonate, and other salts.

[0399] Intramuscular preparations, e.g. a sterile formulation of a suitable soluble salt form of the compounds of the present invention, can be dissolved and administered in a pharmaceutical excipient such as Water-for-Injection, 0.9% saline, or 5% glucose solution. Alternatively, a suitable insoluble form of the compound can be prepared and administered as a suspension in an aqueous base or a pharmaceutically acceptable oil base, such as an ester of a long chain fatty acid (e.g., ethyl oleate), fatty oils such as sesame oil, triglycerides, or liposomes.

[0400] Parenteral formulations of the compositions can contain various carriers such as vegetable oils, dimethylacetamide, dimethylformamide, ethyl lactate, ethyl carbonate, isopropyl myristate, ethanol, polyols (glycerol, propylene glycol, liquid polyethylene glycol, and the like).

[0401] Aqueous injection suspensions can also contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Non-lipid polycationic amino polymers can also be used for delivery. Optionally, the suspension can also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

[0402] Pharmaceutical compositions of the present invention can also be formulated to permit injectable, long-term, deposition. Injectable depot forms may be made by forming microencapsulated matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in microemulsions that are compatible with body tissues.

[0403] The pharmaceutical compositions of the present invention can be administered topically.

[0404] For topical use the compounds of the present invention can also be prepared in suitable forms to be applied to the skin, or mucus membranes of the nose and throat, and can take the form of lotions, creams, ointments, liquid sprays or inhalants, drops, tinctures, lozenges, or throat paints. Such topical formulations further can include chemical compounds such as dimethylsulfoxide (DMSO) to facilitate surface penetration of the active ingredient. In other transdermal formulations, typically in patch-delivered formulations, the pharmaceutically active compound is formulated with one or more skin penetrants, such as 2-N-methyl-pyrrolidone (NMP) or Azone. A topical semi-solid ointment formulation typically contains a concentration of the active ingredient from about 1 to 20%, e.g., 5 to 10%, in a carrier such as a pharmaceutical cream base.

[0405] For application to the eyes or ears, the compounds of the present invention can be presented in liquid or semi-liquid form formulated in hydrophobic or hydrophilic bases as ointments, creams, lotions, paints or powders.

[0406] For rectal administration the compounds of the present invention can be administered in the form of suppositories admixed with conventional carriers such as cocoa butter, wax or other glyceride.

[0407] Inhalation formulations can also readily be formulated. For inhalation, various powder and liquid formulations can be prepared. For aerosol preparations, a sterile formulation of the compound or salt form of the compound may be used in inhalers, such as metered dose inhalers, and nebulizers. Aerosolized forms may be especially useful for treating respiratory disorders.

[0408] Alternatively, the compounds of the present invention can be in powder form for reconstitution in the appropriate pharmaceutically acceptable carrier at the time of delivery.

[0409] The pharmaceutically active compound in the pharmaceutical compositions of the present invention can be provided as the salt of a variety of acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, and succinic acid. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free base forms.

[0410] After pharmaceutical compositions have been prepared, they are packaged in an appropriate container and labeled for treatment of an indicated condition.

[0411] The active compound will be present in an amount effective to achieve the intended purpose. The determination of an effective dose is well within the capability of those skilled in the art.

[0412] A “therapeutically effective dose” refers to that amount of active ingredient, for example LSP polypeptide, fusion protein, or fragments thereof, antibodies specific for LSP, agonists, antagonists or inhibitors of LSP, which ameliorates the signs or symptoms of the disease or prevents progression thereof; as would be understood in the medical arts, cure, although desired, is not required.

[0413] The therapeutically effective dose of the pharmaceutical agents of the present invention can be estimated initially by in vitro tests, such as cell culture assays, followed by assay in model animals, usually mice, rats, rabbits, dogs, or pigs. The animal model can also be used to determine an initial preferred concentration range and route of administration.

[0414] For example, the ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population) can be determined in one or more cell culture of animal model systems. The dose ratio of toxic to therapeutic effects is the therapeutic index, which can be expressed as LD50/ED50. Pharmaceutical compositions that exhibit large therapeutic indices are preferred.

[0415] The data obtained from cell culture assays and animal studies are used in formulating an initial dosage range for human use, and preferably provide a range of circulating concentrations that includes the ED50 with little or no toxicity. After administration, or between successive administrations, the circulating concentration of active agent varies within this range depending upon pharmacokinetic factors well-known in the art, such as the dosage form employed, sensitivity of the patient, and the route of administration.

[0416] The exact dosage will be determined by the practitioner, in light of factors specific to the subject requiring treatment. Factors that can be taken into account by the practitioner include the severity of the disease state, general health of the subject, age, weight, gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. Long-acting pharmaceutical compositions can be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.

[0417] Normal dosage amounts may vary from 0.1 to 100,000 micrograms, up to a total dose of about 1 g, depending upon the route of administration. Where the therapeutic agent is a protein or antibody of the present invention, the therapeutic protein or antibody agent typically is administered at a daily dosage of 0.01 mg to 30 mg/kg of body weight of the patient (e.g., 1 mg/kg to 5 mg/kg). The pharmaceutical formulation can be administered in multiple doses per day, if desired, to achieve the total desired daily dose.

[0418] Guidance as to particular dosages and methods of delivery is provided in the literature and generally available to practitioners in the art. Those skilled in the art will employ different formulations for nucleotides than for proteins or their inhibitors. Similarly, delivery of polynucleotides or polypeptides will be specific to particular cells, conditions, locations, etc.

[0419] Conventional methods, known to those of ordinary skill in the art of medicine, can be used to administer the pharmaceutical formulation(s) of the present invention to the patient. The pharmaceutical compositions of the present invention can be administered alone, or in combination with other therapeutic agents or interventions.

[0420] Therapeutic Methods

[0421] The present invention further provides methods of treating subjects having defects in a gene of the invention, e.g., in expression, activity, distribution, localization, and/or solubility, which can manifest as a disorder of lung function. As used herein, “treating” includes all medically-acceptable types of therapeutic intervention, including palliation and prophylaxis (prevention) of disease. The term “treating” encompasses any improvement of a disease, including minor improvements. These methods are discussed below.

[0422] Gene Therapy and Vaccines

[0423] The isolated nucleic acids of the present invention can also be used to drive in vivo expression of the polypeptides of the present invention. In vivo expression can be driven from a vector, typically a viral vector, often a vector based upon a replication incompetent retrovirus, an adenovirus, or an adeno-associated virus (AAV), for purpose of gene therapy. In vivo expression can also be driven from signals endogenous to the nucleic acid or from a vector, often a plasmid vector, such as pVAXI (Invitrogen, Carlsbad, Calif., USA), for purpose of “naked” nucleic acid vaccination, as further described in U.S. Pat. Nos. 5,589,466; 5,679,647; 5,804,566; 5,830,877; 5,843,913; 5,880,104; 5,958,891; 5,985,847; 6,017,897; 6,110,898; and 6,204,250, the disclosures of which are incorporated herein by reference in their entireties. For cancer therapy, it is preferred that the vector also be tumor-selective. See, e.g., Doronin et al., J. Virol. 75: 3314-24 (2001).

[0424] In another embodiment of the therapeutic methods of the present invention, a therapeutically effective amount of a pharmaceutical composition comprising a nucleic acid of the present invention is administered. The nucleic acid can be delivered in a vector that drives expression of an LSP, fusion protein, or fragment thereof, or without such vector. Nucleic acid compositions that can drive expression of an LSP are administered, for example, to complement a deficiency in the native LSP, or as DNA vaccines. Expression vectors derived from virus, replication deficient retroviruses, adenovirus, adeno-associated (AAV) virus, herpes virus, or vaccinia virus can be used as can plasmids. See, e.g., Cid-Arregui, supra. In a preferred embodiment, the nucleic acid molecule encodes an LSP having the amino acid sequence of SEQ ID NO: 165 through 284, or a fragment, fusion protein, allelic variant or homolog thereof.

[0425] In still other therapeutic methods of the present invention, pharmaceutical compositions comprising host cells that express an LSP, fusions, or fragments thereof can be administered. In such cases, the cells are typically autologous, so as to circumvent xenogeneic or allotypic rejection, and are administered to complement defects in LSP production or activity. In a preferred embodiment, the nucleic acid molecules in the cells encode an LSP having the amino acid sequence of SEQ ID NO: 165 through 284, or a fragment, fusion protein, allelic variant or homolog thereof.

[0426] Antisense Administration

[0427] Antisense nucleic acid compositions, or vectors that drive expression of an LSG antisense nucleic acid, are administered to downregulate transcription and/or translation of an LSG in circumstances in which excessive production, or production of aberrant protein, is the pathophysiologic basis of disease.

[0428] Antisense compositions useful in therapy can have a sequence that is complementary to coding or to noncoding regions of an LSG. For example, oligonucleotides derived from the transcription initiation site, e.g., between positions −10 and +10 from the start site, are preferred.

[0429] Catalytic antisense compositions, such as ribozymes, that are capable of sequence-specific hybridization to LSG transcripts, are also useful in therapy. See, e.g., Phylactou, Adv. Drug Deliv. Rev. 44(2-3): 97-108 (2000); Phylactou et al., Hum. Mol. Genet. 7(10): 1649-53 (1998); Rossi, Ciba Found. Symp. 209: 195-204 (1997); and Sigurdsson et al., Trends Biotechnol. 13(8): 286-9 (1995), the disclosures of which are incorporated herein by reference in their entireties.

[0430] Other nucleic acids useful in the therapeutic methods of the present invention are those that are capable of triplex helix formation in or near the LSG genomic locus. Such triplexing oligonucleotides are able to inhibit transcription. See, e.g., Intody et al., Nucleic Acids Res. 28(21): 4283-90 (2000); McGuffie et al., Cancer Res. 60(14): 3790-9 (2000), the disclosures of which are incorporated herein by reference. Pharmaceutical compositions comprising such triplex forming oligos (TFOs) are administered in circumstances in which excessive production, or production of aberrant protein, is a pathophysiologic basis of disease.

[0431] In a preferred embodiment, the antisense molecule is derived from a nucleic acid molecule encoding an LSP, preferably an LSP comprising an amino acid sequence of SEQ ID NO: 165 through 284, or a fragment, allelic variant or homolog thereof. In a more preferred embodiment, the antisense molecule is derived from a nucleic acid molecule having a nucleotide sequence of SEQ ID NO: 1 through 164, or a part, allelic variant, substantially similar or hybridizing nucleic acid thereof.

[0432] Polypeptide Administration

[0433] In one embodiment of the therapeutic methods of the present invention, a therapeutically effective amount of a pharmaceutical composition comprising an LSP, a fusion protein, fragment, analog or derivative thereof is administered to a subject with a clinically-significant LSP defect.

[0434] Protein compositions are administered, for example, to complement a deficiency in native LSP. In other embodiments, protein compositions are administered as a vaccine to elicit a humoral and/or cellular immune response to LSP. The immune response can be used to modulate activity of LSP or, depending on the immunogen, to immunize against aberrant or aberrantly expressed forms, such as mutant or inappropriately expressed isoforms. In yet other embodiments, protein fusions having a toxic moiety are administered to ablate cells that aberrantly accumulate LSP.

[0435] In a preferred embodiment, the polypeptide is an LSP comprising an amino acid sequence of SEQ ID NO: 165 through 284, or a fusion protein, allelic variant, homolog, analog or derivative thereof. In a more preferred embodiment, the polypeptide is encoded by a nucleic acid molecule having a nucleotide sequence of SEQ ID NO: 1 through 164, or a part, allelic variant, substantially similar or hybridizing nucleic acid thereof.

[0436] Antibody, Agonist and Antagonist Administration

[0437] In another embodiment of the therapeutic methods of the present invention, a therapeutically effective amount of a pharmaceutical composition comprising an antibody (including fragment or derivative thereof) of the present invention is administered. As is well-known, antibody compositions are administered, for example, to antagonize activity of LSP, or to target therapeutic agents to sites of LSP presence and/or accumulation. In a preferred embodiment, the antibody specifically binds to an LSP comprising an amino acid sequence of SEQ ID NO: 165 through 284, or a fusion protein, allelic variant, homolog, analog or derivative thereof. In a more preferred embodiment, the antibody specifically binds to an LSP encoded by a nucleic acid molecule having a nucleotide sequence of SEQ ID NO: 1 through 164, or a part, allelic variant, substantially similar or hybridizing nucleic acid thereof.

[0438] The present invention also provides methods for identifying modulators which bind to an LSP or have a modulatory effect on the expression or activity of an LSP. Modulators which decrease the expression or activity of LSP (antagonists) are believed to be useful in treating lung cancer. Such screening assays are known to those of skill in the art and include, without limitation, cell-based assays and cell-free assays. Small molecules predicted via computer imaging to specifically bind to regions of an LSP can also be designed, synthesized and tested for use in the imaging and treatment of lung cancer. Further, libraries of molecules can be screened for potential anticancer agents by assessing the ability of the molecule to bind to the LSPs identified herein. Molecules identified in the library as being capable of binding to an LSP are key candidates for further evaluation for use in the treatment of lung cancer. In a preferred embodiment, these molecules will downregulate expression and/or activity of an LSP in cells.

[0439] In another embodiment of the therapeutic methods of the present invention, a pharmaceutical composition comprising a non-antibody antagonist of LSP is administered. Antagonists of LSP can be produced using methods generally known in the art. In particular, purified LSP can be used to screen libraries of pharmaceutical agents, often combinatorial libraries of small molecules, to identify those that specifically bind and antagonize at least one activity of an LSP.

[0440] In other embodiments a pharmaceutical composition comprising an agonist of an LSP is administered. Agonists can be identified using methods analogous to those used to identify antagonists.

[0441] In a preferred embodiment, the antagonist or agonist specifically binds to and antagonizes or agonizes, respectively, an LSP comprising an amino acid sequence of SEQ ID NO: 165 through 284, or a fusion protein, allelic variant, homolog, analog or derivative thereof. In a more preferred embodiment, the antagonist or agonist specifically binds to and antagonizes or agonizes, respectively, an LSP encoded by a nucleic acid molecule having a nucleotide sequence of SEQ ID NO: 1 through 164, or a part, allelic variant, substantially similar or hybridizing nucleic acid thereof. Targeting Lung Tissue The invention also provides a method in which a polypeptide of the invention, or an antibody thereto, is linked to a therapeutic agent such that it can be delivered to the lung or to specific cells in the lung. In a preferred embodiment, an anti-LSP antibody is linked to a therapeutic agent and is administered to a patient in need of such therapeutic agent. The therapeutic agent may be a toxin, if lung tissue needs to be selectively destroyed. This would be useful for targeting and killing lung cancer cells. In another embodiment, the therapeutic agent may be a growth or differentiation factor, which would be useful for promoting lung cell function.

[0442] In another embodiment, an anti-LSP antibody may be linked to an imaging agent that can be detected using, e.g., magnetic resonance imaging, CT or PET. This would be useful for determining and monitoring lung function, identifying lung cancer tumors, and identifying noncancerous lung diseases.

EXAMPLES Example 1 Gene Expression Analysis

[0443] LSGs were identified by mRNA subtraction analysis using standard methods. The sequences were extended using GeneBank sequences, Incyte's proprietary database. From the nucleotide sequences, predicted amino acid sequences were prepared. DEX0291_(—)1, DEX0291_(—)2 correspond to SEQ ID NO.1, 2 etc. DEX0134 was the parent sequence found in the mRNA subtractions. DEX0291_1 DEX0134_1 DEX0291_165 DEX0291_2 flex DEX0134_1 DEX0291_3 DEX0134_2 DEX0291_166 DEX0291_4 flex DEX0134_2 DEX0291_5 DEX0134_3 DEX0291_167 DEX0291_6 flex DEX0134_3 DEX0291_168 DEX0291_7 DEX0134_4 DEX0291_169 DEX0291_8 flex DEX0134_4 DEX0291_170 DEX0291_9 DEX0134_5 DEX0291_171 DEX0291_10 flex DEX0134_5 DEX0291_11 DEX0134_6 DEX0291_172 DEX0291_12 flexDEX0134_6 DEX0291_13 DEX0134_7 DBX0291_173 DEX0291_14 flex DEX0134_7 DEX0291_15 DEX0134_8 DEX0291_174 DEX0291_16 flexDEX0134_8 DEX0291_175 DEX0291_17 DEX0134_9 DEX0291_18 DEX0134_10 DEX0291_176 DEX0291_19 DEX0134_11 DEX0291_177 DEX0291_20 flex DEX0134_11 DEX0291_21 DEX0134_12 DEX0291_178 DEX0291_22 flex DEX0134_12 DEX0291_179 DEX0291_23 DEX0134_13 DEX0291_180 DEX0291_24 DEX0134_14 DEX0291_181 DEX0291_25 DEX0134_15 DEX0291_182 DEX0291_26 flex DEX0134_15 DEX0291_183 DEX0291_27 DEX0134_16 DEX0291_184 DEX0291_28 flex DEX0134_16 DEX0291_185 DEX0291_29 DEX0134_17 DEX0291_186 DEX0291_30 flex DEX0134_17 DEX0291_187 DEX0291_31 DEX0134_18 DEX0291_188 DEX0291_32 DEX0134_19 DEX0291_189 DEX0291_33 DEX0134_20 DEX0291_190 DEX0291_34 flex DEX0134_20 DEX0291_191 DEX0291_35 DEX0134_21 DEX0291_192 DEX0291_36 flex DEX0134_21 DEX0291_37 DEX0134_22 DEX0291_193 DEX0291_38 flex DEX0134_22 DEX0291_194 DEX0291_39 DEX0134_23 DEX0291_40 DFXO134_24 DEX0291_195 DEX0291_41 DEX0134_25 DEX0291_42 DEX0134_27 DEX0291_196 DEX0291_43 flex DEX0134_27 DEX0291_44 DEX0134_28 DEX0291_45 DEX0134_29 DEX0291_197 DEX0291_46 flex DEX0134_29 DEX0291_198 DEX0291_47 DEX0134_30 DEX0291_199 DEX0291_48 flex DEX0134_30 DEX0291_200 DEX0291_49 DEX0134_31 DEX0291_201 DEX0291_50 flex DEX0134_31 DEX0291_51 DEX0134_32 DEX0291_202 DEX0291_52 DEX0134_33 DEX0291_53 DEX0134_34 DEX0291_203 DEX0291_54 flex DEX0134_34 DEX0291_204 DEX0291_55 DEX0134_35 DEX0291_205 DEX0291_56 flex DEX0134_35 DEX0291_206 DEX0291_57 DEX0134_36 DEX0291_207 DEX0291_58 flex DEX0134_36 DEX0291_208 DEX0291_59 DEX0134_37 DEX0291_209 DEX0291_60 flex DEX0134_37 DEX0291_210 DEX0291_61 DEX0134_38 DEX0291_211 DEX0291_62 flex DEX0134_38 DEX0291_212 DEX0291_63 DEX0134_39 DEX0291_213 DEX0291_64 flex DEX0134_39 DEX0291_65 DEX0134_40 DEX0291_214 DEX0291_66 flex DEX0134_40 DEX0291_67 DEX0134_41 DEX0291_215 DEX0291_68 flex DEX0134_41 DEX0291_69 DEX0134_42 DEX0291_216 DEX0291_70 flex DEX0134_42 DEX0291_71 DEX0134_43 DEX0291_72 DEX0134_44 DEX0291_217 DEX0291_73 flex DEX0134_44 DEX0291_218 DEX0291_74 DEX0134_46 DEX0291_75 flex DEX0134_46 DEX0291_76 DEX0134_47 DEX0291_219 DEX0291_77 flex DEX0134_47 DEX0291_220 DEX0291_78 DEX0134_48 DEX0291_221 DEX0291_79 flex DEX0134_48 DEX0291_222 DEX0291_80 DEX0134_49 DEX0291_223 DEX0291_81 flex DEX0134_49 DEX0291_224 DEX0291_82 DEX0134_51 DEX0291_225 DEX0291_83 flex DEX0134_51 DEX0291_84 DEX0134_52 DEX0291_226 DEX0291_85 flex DEX0134_52 DEX0291_86 DEX0134_53 DEX0291_227 DEX0291_87 flex DEX0134_53 DEX0291_228 DEX0291_88 DEX0134_54 DEX0291_229 DEX0291_89 flex DEX0134_54 DEX0291_230 DEX0291_90 DEX0134_55 DEX0291_231 DEX0291_91 flex DEX0134_55 DEX0291_92 DEX0134_56 DEX0291_232 DEX0291_93 flex DEX0134_56 DEX0291_233 DEX0291_94 DEX0134_57 DEX0291_234 DEX0291_95 DEX0134_58 DEX0291_235 DEX0291_96 flex DEX0134_58 DEX0291_97 DEX0134_60 DEX0291_236 DEX0291_98 flex DEX0134_60 DEX0291_99 DEX0134_61 DEX0291_237 DEX0291_100 flex DEX0134_61 DEX0291_101 DEX0134_62 DEX0291_238 DEX0291_102 flex DEX0134_62 DEX0291_239 DEX0291_103 DEX0134_63 DEX0291_240 DEX0291_104 DEX0134_64 DEX0291_241 DEX0291_105 flex DEX0134_64 DEX0291_106 DEX0134_65 DEX0291_242 DEX0291_107 flex DEX0134_65 DEX0291_243 DEX0291_108 DEX0134_66 DEX0291_244 DEX0291_109 flex DEX0134_66 DEX0291_110 DEX0134_67 DEX0291_111 flex DEX0134_67 DEX0291_245 DEX0291_112 DEX0134_68 DEX0291_246 DEX0291_113 flexDEX0134_68 DEX0291_247 DEX0291_114 DEX0134_69 DEX0291_248 DEX0291_115 flex DEX0134_69 DEX0291_249 DEX0291_116 DEX0134_70 DEX0291_250 DEX0291_117 flexDEX0134_70 DEX0291_251 DEX0291_118 DEX0134_71 DEX0291_252 DEX0291_119 DEX0134_72 DEX0291_253 DEX0291_120 flex DEX0134_72 DEX0291_121 DEX0134_73 DEX0291_254 DEX0291_122 flex DEX0134_73 DEX0291_255 DEX0291_123 DEX0134_74 DEX0291_256 DEX0291_124 flex DEX0134_74 DEX0291_125 DEX0134_75 DEX0291_257 DEX0291_126 flex DEX0134_75 DEX0291_127 DEX0134_76 DEX0291_258 DEX0291_128 flex DEX0134_76 DEX0291_259 DEX0291_129 DEX0134_77 DEX0291_260 DEX0291_130 flex DEX0134_77 DEX0291_131 DEX0134_78 DEX0291_261 DEX0291_132 flex DEX0134_78 DEX0291_133 DEX0134_79 DEX0291_262 DEX0291_134 DEX0134_80 DEX0291_263 DEX0291_135 flex DEX0134_80 DEX0291_264 DEX0291_136 DEX0134_81 DEX0291_265 DEX0291_137 DEX0134_82 DEX0291_266 DEX0291_138 DEX0134_83 DEX0291_267 DEX0291_139 flex DEX0134_83 DEX0291_140 DEX0134_84 DEX0291_268 DEX0291_141 flex DEX0134_84 DEX0291_142 DEX0134_85 DEX0291_269 DEX0291_143 DEX0134_86 DEX0291_270 DEX0291_144 flex DEX0134_86 DEX0291_145 DEX0134_87 DEX0291_146 DEX0134_88 DEX0291_271 DEX0291_147 DEX0134_89 DEX0291_272 DEX0291_148 flex DEX0134_89 DEX0291_149 DEX0134_90 DEX0291_273 DEX0291_150 flex DEX0134_90 DEX0291_274 DEX0291_151 DEX0134_91 DEX0291_275 DEX0291_152 flexDEX0134_91 DEX0291_153 DEX0134_92 DEX0291_276 DEX0291_154 flex DEX0134_92 DEX0291_155 DEX0134_93 DEX0291_277 DEX0291_156 flex DEX0134_93 DEX0291_157 DEX0134_94 DEX0291_158 DEX0134_95 DEX0291_278 DEX0291_159 DEX0134_96 DEX0291_279 DEX0291_160 DEX0134_97 DEX0291_280 DEX0291_161 flex DEX0134_97 DEX0291_281 DEX0291_162 DEX0134_98 DEX0291_282 DEX0291_163 DEX0134_99 DEX0291_283 DEX0291_164 flex DEX0134_99 DEX0291_284 The chromosomal locations were as follows: DEX0291_6 chromosome 14 DEX0291_12 chromosome 2 DEX0291_16 chromosome 19 DEX0291_19 chromosome 17 DEX0291_21 chromosome 1 DEX0291_23 chromosome 12 DEX0291_24 chromosome 16 DEX0291_26 chromosome 10 DEX0291_28 chromosome 4 DEX0291_31 chromosome 11 DEX0291_33 chromosome 11 DEX0291_34 chromosome 11 DEX0291_36 chromosome 5 DEX0291_38 chromosome 11 DEX0291_39 chromosome 16 DEX0291_40 chromosome 13 DEX0291_41 chromosome 13 DEX0291_42 chromosome 10 DEX0291_43 chromosome 10 DEX0291_44 chromosome 7 DEX0291_46 chromosome 12 DEX0291_48 chromosome 10 DEX0291_52 chromosome 7 DEX0291_53 chromosome 7 DEX0291_56 chromosome X DEX0291_58 chromosome 15 DEX0291_59 chromosome 7 DEX0291_60 chromosome 7 DEX0291_61 chromosome 5 DEX0291_62 chromosome 5 DEX0291_68 chromosome 5 DEX0291_70 chromosome 8 DEX0291_73 chromosome 2 DEX0291_77 chromosome 8 DEX0291_78 chromosome 16 DEX0291_79 chromosome 16 DEX0291_85 chromosome 15 DEX0291_89 chromosome 20 DEX0291_91 chromosome 2 DEX0291_93 chromosome 1 DEX0291_94 chromosome 15 DEX0291_98 chromosome 15 DEX0291_99 chromosome 2 DEX0291_101 chromosome 8 DEX0291_102 chromosome 8 DEX0291_107 chromosome 4 DEX0291_111 chromosome 7 DEX0291_118 chromosome 7 DEX0291_123 chromosome 4 DEX0291_124 chromosome 4 DEX0291_127 chromosome 6 DEX0291_128 chromosome 16 DEX0291_131 chromosome 3 DEX0291_132 chromosome 3 DEX0291_135 chromosome 1 DEX0291_138 chromosome 18 DEX0291_139 chromosome 18 DEX0291_141 chromosome 3 DEX0291_142 chromosome 1 DEX0291_146 chromosome 5 DEX0291_150 chromosome 1 DEX0291_151 chromosome 7 DEX0291_152 chromosome 7 DEX0291_153 chromosome 5 DEX0291_156 chromosome 12 DEX0291_160 chromosome 8 DEX0291_161 chromosome 8 DEX0291_162 chromosome 17 DEX0291_163 chromosome 6 DEX0291_164 chromosome 6

[0444] LSGs were also identified by a systematic analysis of gene expression data in the LIFESEQ® Gold database available from Incyte Genomics Inc (Palo Alto, Calif.) using the data mining software package CLASP™ (Candidate Lead Automatic Search Program). CLASP™ is a set of algorithms that interrogate Incyte's database to identify genes that are both specific to particular tissue types as well as differentially expressed in tissues from patients with cancer. LifeSeq® Gold contains information about which genes are expressed in various tissues in the body and about the dynamics of expression in both normal and diseased states. CLASPTM first sorts the LifeSeq® Gold database into defined tissue types, such as breast, ovary and prostate. CLASPTM categorizes each tissue sample by disease state. Disease states include “healthy,” “cancer,” “associated with cancer,” “other disease” and “other.” Categorizing the disease states improves our ability to identify tissue and cancer-specific molecular targets. CLASPTM then performs a simultaneous parallel search for genes that are expressed both (1) selectively in the defined tissue type compared to other tissue types and (2) differentially in the “cancer” disease state compared to the other disease states affecting the same, or different, tissues. This sorting is accomplished by using mathematical and statistical filters that specify the minimum change in expression levels and the minimum frequency that the differential expression pattern must be observed across the tissue samples for the gene to be considered statistically significant. The CLASP™ algorithm quantifies the relative abundance of a particular gene in each tissue type and in each disease state.

[0445] To find the LSGs of this invention, the following specific CLASPTM profiles were utilized: tissue-specific expression (CLASP 1), detectable expression only in cancer tissue (CLASP 2), highest differential expression for a given cancer (CLASP 4); differential expression in cancer tissue (CLASP 5), and. cDNA libraries were divided into 60 unique tissue types (early versions of LifeSeq® had 48 tissue types). Genes or ESTs were grouped into “gene bins,” where each bin is a cluster of sequences grouped together where they share a common contig. The expression level for each gene bin was calculated for each tissue type. Differential expression significance was calculated with rigorous statistical significant testing taking into account variations in sample size and relative gene abundance in different libraries and within each library (for the equations used to determine statistically significant expression see Audic and Clayerie “The significance of digital gene expression profiles,” Genome Res 7(10): 986-995 (1997), including Equation 1 on page 987 and Equation 2 on page 988, the contents of which are incorporated by reference). Differentially expressed tissue-specific genes were selected based on the percentage abundance level in the targeted tissue versus all the other tissues (tissue-specificity). The expression levels for each gene in libraries of normal tissues or non-tumor tissues from cancer patients were compared with the expression levels in tissue libraries associated with tumor or disease (cancer-specificity). The results were analyzed for statistical significance.

[0446] The selection of the target genes meeting the rigorous CLASPTM profile criteria were as follows:

[0447] (a) CLASP 1: tissue-specific expression: To qualify as a CLASP 1 candidate, a gene must exhibit statistically significant expression in the tissue of interest compared to all other tissues. Only if the gene exhibits such differential expression with a 90% of confidence level is it selected as a CLASP 1 candidate.

[0448] (b) CLASP 2: detectable expression only in cancer tissue: To qualify as a CLASP 2 candidate, a gene must exhibit detectable expression in tumor tissues and undetectable expression in libraries from normal individuals and libraries from normal tissue obtained from diseased patients. In addition, such a gene must also exhibit further specificity for the tumor tissues of interest.

[0449] (c) CLASP 4: highest differential expression for a given cancer: To qualify as a CLASP 4 candidate, a gene must be differentially expressed in tumor libraries in the tissue of interest compared to normal libraries for all tissues. In addition, it must be one of the 50 genes with the highest differential expression.

[0450] (d) CLASP 5: differential expression in cancer tissue: To qualify as a CLASP 5 candidate, a gene must be differentially expressed in tumor libraries in the tissue of interest compared to normal libraries for all tissues. Only if the gene exhibits such differential expression with a 90% of confidence level is it selected as a CLASP 5 candidate.

[0451] DEX0291_(—)86 Lung 5 H

[0452] DEX0291_(—)87 Lung 5 H

[0453] The individual tissue expression levels from the Incyte LifeSeq database were as follows: DEX0291_1 SEQ ID NO: 1 UTR.0044 PAN.0059 BMR.0064 TON.0299 DEX0291_10 SEQ ID NO: 10 OVR.0021 PRO.0034 UNC.004 THR.0045 DEX0291_100 SEQ ID NO: 100 LMN.0028 NOS.0073 DEX0291_101 SEQ ID NO: 101 INS.0067 GLB.0139 UTR.0182 NOS.022 DEX0291_104 SEQ ID NO: 104 UTR.0044 PAN.0059 BMR.0064 TON.0299 DEX0291_105 SEQ ID NO: 105 UTR.0044 PAN.0059 BMR.0064 TON.0299 DEX0291_108 SEQ ID NO: 108 LMN.0028 UNC.004 DEX0291_11 SEQ ID NO: 11 FTS.0006 SPL.0021 LNG.0034 INS.0038 DEX0291_110 SEQ ID NO: 110 LIV.0038 THY.004 CRD.0068 DEX0291_112 SEQ ID NO: 112 BLD.0225 DEX0291_113 SEQ ID NO: 113 BLD.0225 DEX0291_114 SEQ ID NO: 114 PNS.0047 CRD.0068 BON.0169 DEX0291_115 SEQ ID NO: 115 PNS.0047 CRD.0068 BON.0169 DEX0291_116 SEQ ID NO: 116 LNG.0006 OVR.001 PRO.0017 BLD.0048 DEX0291_117 SEQ ID NO: 117 LNG.0006 OVR.001 PRO.0017 BLD.0048 DEX0291_118 SEQ ID NO: 118 LNG.0006 LMN.0028 DEX0291_119 SEQ ID NO: 119 PAN.0047 NOS.0073 GLB.0139 DEX0291_12 SEQ ID NO: 12 FTS.0006 SPL.0021 LNG.0034 INS.0038 DEX0291_120 SEQ ID NO: 120 PAN.0047 NOS.0073 GLB.0139 DEX0291_123 SEQ ID NO: 123 UNC.004 NOS.0073 LIV.0076 ADR.0089 DEX0291_124 SEQ ID NO: 124 UNC.004 NOS.0073 LIV.0076 ADR.0089 DEX0291_127 SEQ ID NO: 127 INS.001 BLD.0016 LNG.0017 MAM.0019 DEX0291_128 SEQ ID NO: 128 PNS.007 DEX0291_13 SEQ ID NO: 13 OVR.0154 LNG.0296 DEX0291_131 SEQ ID NO: 131 UTR.0006 LMN.0028 FAL.0063 DEX0291_132 SEQ ID NO: 132 UTR.0006 LMN.0028 FAL.0063 DEX0291_137 SEQ ID NO: 137 LMN.0056 PNS.0094 MAM.0194 FAL.0251 DEX0291_138 SEQ ID NO: 138 INS.001 MAM.0028 UNC.004 FAL.0126 DEX0291_139 SEQ ID NO: 139 INS.001 MAM.0028 UNC.004 FAL.0126 DEX0291_14 SEQ ID NO: 14 OVR.0154 LNG.0296 DEX0291_142 SEQ ID NO: 142 THR.0023 DEX0291_146 SEQ ID NO: 146 PRO.0003 INL.0004 CON.0007 PAN.0008 DEX0291_147 SEQ ID NO: 147 UTR.0075 PLE.0449 DEX0291_148 SEQ ID NO: 148 UTR.0075 PLE.0449 DEX0291_15 SEQ ID NO: 15 INS.0789 DEX0291_151 SEQ ID NO: 151 UTR.0006 PAN.0012 DEX0291_152 SEQ ID NO: 152 UTR.0006 PAN.0012 DEX0291_155 SEQ ID NO: 155 BLV.0016 PRO.0017 MAM.0019 PNS.0023 DEX0291_158 SEQ ID NO: 158 OVR.0021 KID.0039 GLB.0046 FAL.0063 DEX0291_160 SEQ ID NO: 160 THY.002 DEX0291_161 SEQ ID NO: 161 THY.002 DEX0291_18 SEQ ID NO: 18 BRN.0006 FAL.0063 DEX0291_19 SEQ ID NO: 19 UTR.0063 LMN.0167 BON.0225 DEX0291_2 SEQ ID NO: 2 UTR.0044 PAN.0059 BMR.0064 TON.0299 DEX0291_20 SEQ ID NO: 20 UTR.0063 LMN.0167 BON.0225 DEX0291_21 SEQ ID NO: 21 PAN.0353 LMN.0416 OVR.0503 INT.1052 DEX0291_22 SEQ ID NO: 22 PAN.0353 LMN.0416 OVR.0503 INT.1052 DEX0291_23 SEQ ID NO: 23 CRD.0114 KID.0128 ADR.0209 PLE.0449 DEX0291_25 SEQ ID NO: 25 LIV.0057 DEX0291_26 SEQ ID NO: 26 LIV.0057 DEX0291_27 SEQ ID NO: 27 PRO.0034 FAL.0063 DEX0291_29 SEQ ID NO: 29 UTR.0013 ADR.0015 DEX0291_33 SEQ ID NO: 33 MAM.0005 LNG.0006 ADR.0015 BLV.0016 DEX0291_34 SEQ ID NO: 34 MAM.0005 LNG.0006 ADR.0015 BLV.0016 DEX0291_37 SEQ ID NO: 37 BRN.0031 THR.0045 DEX0291_38 SEQ ID NO: 38 BRN.0031 THR.0045 DEX0291_45 SEQ ID NO: 45 GLB.0093 DEX0291_47 SEQ ID NO: 47 PNS.0047 CRD.0068 BON.0169 DEX0291_48 SEQ ID NO: 48 PNS.0047 CRD.0068 BON.0169 DEX0291_49 SEQ ID NO: 49 UTR.0263 NOS.066 DEX0291_5 SEQ ID NO: 5 THR.0091 BMR.0129 LMN.0139 DEX0291_51 SEQ ID NO: 51 LIV.0019 OVR.0031 URE.0112 DEX0291_53 SEQ ID NO: 53 PAN.0071 NOS.0073 LMN.0083 PRO.0119 DEX0291_54 SEQ ID NO: 54 PAN.0071 NOS.0073 LMN.0083 PRO.0119 DEX0291_55 SEQ ID NO: 55 LNG.0006 OVR.001 PRO.0017 BLD.0048 DEX0291_56 SEQ ID NO: 56 LNG.0006 OVR.001 PRO.0017 BLD.0048 DEX0291_59 SEQ ID NO: 59 SPL.0042 DEX0291_65 SEQ ID NO: 65 FTS.0012 INS.0019 SPL.0021 KID.009 DEX0291_66 SEQ ID NO: 66 FTS.0012 INS.0019 SPL.0021 KID.009 DEX0291_67 SEQ ID NO: 67 BRN.0023 LIV.0038 URE.0112 DEX0291_68 SEQ ID NO: 68 BRN.0023 LIV.0038 URE.0112 DEX0291_7 SEQ ID NO: 7 CON.0011 DEX0291_70 SEQ ID NO: 70 CRD.0023 BLD.0064 DEX0291_71 SEQ ID NO: 71 PRO.0003 UTR.0004 BLO.0006 PRO.0006 DEX0291_72 SEQ ID NO: 72 CON.0113 LIV.0189 ADR.0209 DEX0291_74 SEQ ID NO: 74 CON.0113 LIV.0189 ADR.0209 DEX0291_75 SEQ ID NO: 75 CON.0113 LIV.0189 ADR.0209 DEX0291_78 SEQ ID NO: 78 THY.006 KID.009 GLB.0093 LIV.0132 DEX0291_79 SEQ ID NO: 79 THY.006 KID.009 GLB.0093 LIV.0132 DEX0291_8 SEQ ID NO: 8 CON.0011 DEX0291_80 SEQ ID NO: 80 NOS.0073 STO.0081 ESO.0102 DEX0291_86 SEQ ID NO: 86 BLO.0006 BLV.0006 INL.0012 LNG.0017 DEX0291_87 SEQ ID NO: 87 BLO.0006 BLV.0006 INL.0012 LNG.0017 DEX0291_88 SEQ ID NO: 88 CRD.0023 PNS.0047 INT.015 URE.0225 DEX0291_89 SEQ ID NO: 89 CRD.0023 PNS.0047 INT.015 URE.0225 DEX0291_9 SEQ ID NO: 9 OVR.0021 PRO.0034 UNC.004 THR.0045 DEX0291_90 SEQ ID NO: 90 LMN.0028 NOS.0073 DEX0291_91 SEQ ID NO: 91 LMN.0028 NOS.0073 DEX0291_92 SEQ ID NO: 92 INL.0045 DEX0291_93 SEQ ID NO: 93 INL.0045 DEX0291_95 SEQ ID NO: 95 CRD.0023 BLD.0064 DEX0291_97 SEQ ID NO: 97 ADR.0104 KID.0141 PLE.015 DEX0291_98 SEQ ID NO: 98 ADR.0104 KID.0141 PLE.015 DEX0291_99 SEQ ID NO: 99 LMN.0028 NOS.0073

[0454] Abbreviation for tissues:

[0455] BLO Blood; BRN Brain; CON Connective Tissue; CRD Heart; FTS Fetus; INL Intestine, Large; INS Intestine, Small; KID Kidney; LIV Liver; LNG Lung; MAM Breast; MSL Muscles; NRV Nervous Tissue; OVR Ovary; PRO Prostate; STO Stomach; THR Thyroid Gland; TNS Tonsil/Adenoids; UTR Uterus

Example 2 Relative Quantitation of Gene Expression

[0456] Real-Time quantitative PCR with fluorescent Taqman probes is a quantitation detection system utilizing the 5′-3′ nuclease activity of Taq DNA polymerase. The method uses an internal fluorescent oligonucleotide probe (Taqman) labeled with a 5′ reporter dye and a downstream, 3′ quencher dye. During PCR, the 5′-3′ nuclease activity of Taq DNA polymerase releases the reporter, whose fluorescence can then be detected by the laser detector of the Model 7700 Sequence Detection System (PE Applied Biosystems, Foster City, Calif., USA). Amplification of an endogenous control is used to standardize the amount of sample RNA added to the reaction and normalize for Reverse Transcriptase (RT) efficiency. Either cyclophilin, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), ATPase, or 18S ribosomal RNA (rRNA) is used as this endogenous control. To calculate relative quantitation between all the samples studied, the target RNA levels for one sample were used as the basis for comparative results (calibrator). Quantitation relative to the “calibrator” can be obtained using the standard curve method or the comparative method (User Bulletin #2: ABI PRISM 7700 Sequence Detection System).

[0457] The tissue distribution and the level of the target gene are evaluated for every sample in normal and cancer tissues. Total RNA is extracted from normal tissues, cancer tissues, and from cancers and the corresponding matched adjacent tissues. Subsequently, first strand cDNA is prepared with reverse transcriptase and the polymerase chain reaction is done using primers and Taqman probes specific to each target gene. The results are analyzed using the ABI PRISM 7700 Sequence Detector. The absolute numbers are relative levels of expression of the target gene in a particular tissue compared to the calibrator tissue.

[0458] One of ordinary skill can design appropriate primers. The relative levels of expression of the LSNA versus normal tissues and other cancer tissues can then be determined. All the values are compared to normal tissue (calibrator). These RNA samples are commercially available pools, originated by pooling samples of a particular tissue from different individuals.

[0459] The relative levels of expression of the LSNA in pairs of matching samples and 1 cancer and 1 normal/normal adjacent of tissue may also be determined. All the values are compared to normal tissue (calibrator). A matching pair is formed by mRNA from the cancer sample for a particular tissue and mRNA from the normal adjacent sample for that same tissue from the same individual.

[0460] In the analysis of matching samples, the LSNAs show a high degree of tissue specificity for the tissue of interest. These results confirm the tissue specificity results obtained with normal pooled samples.

[0461] Further, the level of mRNA expression in cancer samples and the isogenic normal adjacent tissue from the same individual are compared. This comparison provides an indication of specificity for the cancer stage (e.g. higher levels of mRNA expression in the cancer sample compared to the normal adjacent).

[0462] Altogether, the high level of tissue specificity, plus the mRNA overexpression in matching samples tested are indicative of SEQ ID NO: 1 through 164 being diagnostic markers for cancer. Sequences Sequence ID ddx QPCR code DEX0134_10 DEX0291_18 Lng261 DEX0134_17 DEX0291_29 Lng262 DEX0291_30 DEX0134_2 DEX0291_3 Lng259 DEX0291_4 DEX0134_24 DEX0291_40 Lng260 DEX0134_77 DEX0291_129 Lng264 DEX0291_130 DEX0134_80 DEX0291_134 Lng256 DEX0291_135 DEX0134_96 DEX0291_159 Lng228

[0463] Experiments are underway to test primers and probes for QPCR.

[0464] DEX0134_(—)17; DEX0291_(—)29(SEQ ID NO: 29); DEX0291_(—)30(SEQ ID NO: 30); Lng262

[0465] Experiments are underway to test primers and probes for QPCR. Primers Used for QPCR Expression Analysis in DEX291_(—)29 Primer Probe Start End Oligo From To queryLength sbjctDescript lng262For 33 50 18 DEX0134_17 lng262Rev 122 101 22 DEX0134_17 lng262Probe 54 74 21 DEX0134_17

[0466] DEX0134_(—)2; DEX0291_(—)3(SEQ ID NO: 3); DEX0291_(—)4(SEQ ID NO:4); Lng259

[0467] Experiments are underway to test primers and probes for QPCR.

[0468] DEX0134 24; DEX0291 40(SEQ ID NO: 40); Lng260

[0469] Experiments are underway to test primers and probes for QPCR.

[0470] DEX0134_(—)77; DEX0291_(—)129(SEQ ID NO: 129); DEX0291 130(SEQ ID NO: 130); Lng264

[0471] Experiments are underway to test primers and probes for QPCR.

[0472] DEX0134_(—)80; DEX0291_(—)134(SEQ ID NO: 134); DEX0291_(—)135(SEQ ID NO: 135); Lng256

[0473] Experiments are underway to test primers and probes for QPCR.

[0474] DEX0134_(—)96; DEX0291_(—)159(SEQ ID NO: 159); Lng228

[0475] Experiments are underway to test primers and probes for QPCR.

[0476] Primers Used for QPCR Expression Analysis Primer Probe Start End Oligo From To queryLength sbjctDescript lng228For 814 837 24 DEX0134_96 lng228Rev 940 917 24 DEX0134_96 lng228Probe 906 877 30 DEX0134_96

Example 3 Protein Expression

[0477] The LSNA is amplified by polymerase chain reaction (PCR) and the amplified DNA fragment encoding the LSNA is subcloned in pET-21d for expression in E. coli. In addition to the LSNA coding sequence, codons for two amino acids, Met-Ala, flanking the NH₂-terminus of the coding sequence of LSNA, and six histidines, flanking the COOH-terminus of the coding sequence of LSNA, are incorporated to serve as initiating Met/restriction site and purification tag, respectively.

[0478] An over-expressed protein band of the appropriate molecular weight may be observed on a Coomassie blue stained polyacrylamide gel. This protein band is confirmed by Western blot analysis using monoclonal antibody against 6X Histidine tag.

[0479] Large-scale purification of LSP was achieved using cell paste generated from 6-liter bacterial cultures, and purified using immobilized metal affinity chromatography (IMAC). Soluble fractions that had been separated from total cell lysate were incubated with a nickle chelating resin. The column was packed and washed with five column volumes of wash buffer. LSP was eluted stepwise with various concentration imidazole buffers.

Example 4 Protein Fusions

[0480] Briefly, the human Fc portion of the IgG molecule can be PCR amplified, using primers that span the 5′ and 3′ ends of the sequence described below. These primers also should have convenient restriction enzyme sites that will facilitate cloning into an expression vector, preferably a mammalian expression vector. For example, if pC4 (Accession No. 209646) is used, the human Fc portion can be ligated into the BamHI cloning site. Note that the 3′ BamHI site should be destroyed. Next, the vector containing the human Fc portion is re-restricted with BamHI, linearizing the vector, and a polynucleotide of the present invention, isolated by the PCR protocol described in Example 2, is ligated into this BamHI site. Note that the polynucleotide is cloned without a stop codon, otherwise a fusion protein will not be produced. If the naturally occurring signal sequence is used to produce the secreted protein, pC4 does not need a second signal peptide. Alternatively, if the naturally occurring signal sequence is not used, the vector can be modified to include a heterologous signal sequence. See, e.g., WO 96/34891.

Example 5 Production of an Antibody from a Polypeptide

[0481] In general, such procedures involve immunizing an animal (preferably a mouse) with polypeptide or, more preferably, with a secreted polypeptide-expressing cell. Such cells may be cultured in any suitable tissue culture medium; however, it is preferable to culture cells in Earle's modified Eagle's medium supplemented with 10% fetal bovine serum (inactivated at about 56° C.), and supplemented with about 10 g/l of nonessential amino acids, about 1,000 U/ml of penicillin, and about 100 μg/ml of streptomycin. The splenocytes of such mice are extracted and fused with a suitable myeloma cell line. Any suitable myeloma cell line may be employed in accordance with the present invention; however, it is preferable to employ the parent myeloma cell line (SP20), available from the ATCC. After fusion, the resulting hybridoma cells are selectively maintained in HAT medium, and then cloned by limiting dilution as described by Wands et al., Gastroenterology 80: 225-232 (1981).

[0482] The hybridoma cells obtained through such a selection are then assayed to identify clones which secrete antibodies capable of binding the polypeptide. Alternatively, additional antibodies capable of binding to the polypeptide can be produced in a two-step procedure using anti-idiotypic antibodies. Such a method makes use of the fact that antibodies are themselves antigens, and therefore, it is possible to obtain an antibody which binds to a second antibody. In accordance with this method, protein specific antibodies are used to immunize an animal, preferably a mouse. The splenocytes of such an animal are then used to produce hybridoma cells, and the hybridoma cells are screened to identify clones which produce an antibody whose ability to bind to the protein-specific antibody can be blocked by the polypeptide. Such antibodies comprise anti-idiotypic antibodies to the protein specific antibody and can be used to immunize an animal to induce formation of further protein-specific antibodies. Using the Jameson-Wolf methods the following epitopes were predicted. (Jameson and Wolf, CABIOS, 4(1), 181-186, 1988, the contents of which are incorporated by reference). DEX0291_166 Antigenicity Index (Jameson-Wolf) positions AI avg length 21-37 1.23 17 DEX0291_168 Antigenicity Index (Jameson-Wolf) positions AI avg length 69-80 1.07 12 DEX0291_169 Antigenicity Index (Jameson-Wolf) positions AI avg length 15-25 1.06 11 DEX0291_170 Antigenicity Index (Jameson-Wolf) positions AI avg length 54-64 1.06 11 DEX0291_175 Antigenicity Index (Jameson-Wolf) positions AI avg length 166-176 1.36 11 41-65 1.18 25 190-207 1.15 18 71-84 1.03 14 DEX0291_177 Antigenicity Index (Jameson-Wolf) positions AI avg length 42-54 1.12 13 DEX0291_182 Antigenicity Index (Jameson-Wolf) positions AI avg length 35-50 1.20 16 DEX0291_183 Antigenicity Index (Jameson-Wolf) positions AI avg length 48-66 1.16 19 68-87 1.13 20 DEX0291_184 Antigenicity Index (Jameson-Wolf) positions AI avg length 52-93 1.05 42 DEX0291_185 Antigenicity Index (Jameson-Wolf) positions AI avg length 199-209 1.24 11  4-26 1.22 23 322-353 1.09 32 408-462 1.08 55 467-482 1.01 16 30-49 1.01 20 DEX0291_187 Antigenicity Index (Jameson-Wolf) positions AI avg length 67-80 1.15 14 DEX0291_193 Antigenicity Index (Jameson-Wolf) positions AI avg length 5-34 1.13 30 DEX0291_194 Antigenicity Index (Jameson-Wolf) positions AI avg length 58-71 1.33 14 195-210 1.06 16 37-52 1.04 16 DEX0291_196 Antigenicity Index (Jameson-Wolf) positions AI avg length 70-87 1.15 18 DEX0291_199 Antigenicity Index (Jameson-Wolf) positions AI avg length 79-91 1.10 13 DEX0291_200 Antigenicity Index (Jameson-Wolf) positions AI avg length 262-289 1.09 28 225-234 1.07 10 412-426 1.03 15 DEX0291_203 Antigenicity Index (Jameson-Wolf) positions AI avg length 66-77 1.26 12 DEX0291_204 Antigenicity Index (Jameson-Wolf) positions AI avg length 109-141 1.04 33 61-78 1.03 18 46-58 1.00 13 DEX0291_205 Antigenicity Index (Jameson-Wolf) positions AI avg length 12-37 1.03 26 DEX0291_206 Antigenicity Index (Jameson-Wolf) positions AI avg length  91-100 1.19 10 DEX0291_208 Antigenicity Index (Jameson-Wolf) positions AI avg length 33-45 1.18 13 105-122 1.10 18 58-103 1.02 46 DEX0291_212 Antigenicity Index (Jameson-Wolf) positions AI avg length 373-393 1.24 21 70-81 1.20 12 430-457 1.11 28 485-533 1.07 49 204-254 1.06 51 289-314 1.04 26 141-165 1.03 25 462-478 1.03 17 126-135 1.02 10 172-202 1.02 31 318-363 1.02 46 10-34 1.01 25  98-119 1.00 22 DEX0291_216 Antigenicity Index (Jameson-Wolf) positions AI avg length 10-21 1.35 12 DEX0291_218 Antigenicity Index (Jameson-Wolf) positions AI avg length 662-694 1.20 33 36-61 1.12 26  98-118 1.10 21 283-334 1.02 52 699-740 1.01 42 DEX0291_221 Antigenicity Index (Jame son-Wolf) positions AI avg length 20-32 1.17 13 DEX0291_225 Antigenicity Index (Jameson-Wolf) positions AI avg length 61-72 1.16 12  3-58 1.07 56 DEX0291_226 Antigenicity Index (Jameson-Wolf) positions AI avg length  7-20 1.02 14 DEX0291_228 Antigenicity Index (Jameson-Wolf) positions AI avg length 73-83 1.05 11 170-183 1.01 14 DEX0291_238 Antigenicity Index (Jameson-Wolf) positions AI avg length 13-41 1.11 29 DEX0291_239 Antigenicity Index (Jameson-Wolf) positions AI avg length 38-54 1.25 17 DEX0291_241 Antigenicity Index (Jameson-Wolf) positions AI avg length 35-56 1.07 22 DEX0291_243 Antigenicity Index (Jameson-Wolf) positions AI avg length 35-48 1.10 14 DEX0291_245 Antigenicity Index (Jameson-Wolf,) positions AI avg length 144-155 1.04 12 DEX0291_247 Antigenicity Index (Jameson-Wolf) positions AI avg length 44-57 1.14 14 93-107 1.06 15 69-84 1.02 16 DEX0291_249 Antigenicity Index (Jameson-Wolf) positions AI avg length 262-289 1.09 28 225-234 1.07 10 412-426 1.03 15 DEX0291_251 Antigenicity Index (Jameson-Wolf) positions AI avg length  91-100 1.19 10 DEX0291_255 Antigenicity Index (Jameson-Wolf) positions AI avg length 14-25 1.18 12 DEX0291_256 Antigenicity Index (Jameson-Wolf) positions AI avg length 12-21 1.11 10 DEX0291_257 Antigenicity Index (Jameson-Wolf) positions AI avg length 21-31 1.19 11 DEX0291_259 Antigenicity Index (Jameson-Wolf) positions AI avg length 595-607 1.25 13 446-457 1.15 12 80-92 1.09 13 632-641 1.08 10 246-257 1.06 12 1054-1073 1.06 20 336-383 1.05 48 955-975 1.02 21 1477-1505 1.02 29 425-439 1.01 15 DEX0291_264 Antigenicity Index (Jameson-Wolf) positions AI avg length 22-32 1.02 11 DEX0291_276 Antigenicity Index (Jameson-Wolf) positions AI avg length 53-73 1.06 21 DEX0291_280 Antigenicity Index (Jameson-Wolf) positions AI avg length 32-48 1.04 17 DEX0291_281 Antigenicity Index (Jameson-Wolf) positions AI avg length 34-48 1.23 15 DEX0291_282 Antigenicity Index (Jameson-Wolf) positions AI avg length  58-113 1.10 56 DEX0291_284 Antigenicity Index (Jameson-Wolf) positions AI avg length 111-131 1.05 21 The predicted helicities were as follows: DEX0291_169 PredHel = 2 Topology = o24-43i55-77o DEX0291_170 PredHel = 3 Topology = i29-48o63-82i94-116o DEX0291_175 PredHel = 5 Topology = i144-166o209-231i312- 334o349-371i373-3950 DEX0291_183 PredHel = 1 Topology = o20-42i DEX0291_190 PredHel = 1 Topology = i57-79o DEX0291_193 PredHel = 1 Topology = o33-52i DEX0291_195 PredHel = 1 Topology = i21-38o DEX0291_209 PredHel = 1 Topology = o36-58i DEX029T_213 PredHel = 1 Topology = o20-37i DEX0291_218 PredHel = 1 Topology = o616-638i DEX0291_223 PredHel = 2 Topology = o20-42i55-86o DEX0291_229 PredHel = 2 Topology = i5-22o27-45i DEX0291_239 PredHel = 1 Topology = i58-80o DEX0291_247 PredHel = 2 Topology = o20-42i205-227o DEX0291_254 PredHel = 1 Topology = i7-29o DEX0291_259 PredHel = 6 Topology = o761-780i828-850o865- 883i896-918o983-1005i1035- 1052o DEX0291_260 PredHel = 1 Topology = o55-77i DEX0291_262 PredHel = 1 Topalogy = o50-67i DEX0291_270 PredHel = 1 Topology = i20-39o DEX0291_272 PredHel = 1 Topology = o10-32i DEX0291_279 PredHel = 3 Topology = o42-64i99-121o126-148i DEX0291_281 PredHel = 1 Topology = i82-103o DEX0291_283 PredHel = 2 Topology = i13-35o55-77i

[0483] Examples of post-translational modifications (PTMs) of the LSP of this invention are listed below. In addition, antibodies that specifically bind such post-translational modifications may be useful as a diagnostic or as therapeutic. Using the ProSite database (Bairoch et al., Nucleic Acids Res. 25(1):217-221 (1997), the contents of which are incorporated by reference), the following PTMs were predicted for the LSPs of the invention (http://npsa-pbil.ibcp.fr/cgi-bin/npsa_automat.pl?page=npsa_prosite.html most recently accessed Oct. 23, 2001). DEX0291_165 Pkc_Phospho_Site 8-10; DEX0291_166 Asn_Glycosylation 29-32; Ck2_Phospho_Site 9-12; Pkc_Phospho_Site 25-27; 31-33; DEX0291_167 Myristyl 4-9; 30-35; 32-37; Prokar_Lipoprotein 24-34; DEX0291_169 Ck2_Phospho_Site 20-23; Pkc_Phospho_Site 20-22; 90-92; DEX0291_170 Ck2_Phospho_Site 59-62; Pkc_Phospho_Site 2-4; 9-11; 17-19; 21-23; 59-61; DEX0291_172 Ck2_Phospho_Site 29-32; 34-37; Myristyl 10-15; DEX0291_173 Pkc_Phospho_Site 33-35; DEX0291_175 Asn_Glycosylation 191-194; 396-399; Ck2_Phospho_Site 164-167; 308-311; 344- 347; 405-408; 414-417; Leucine_Zipper 291-312; 298-319; Myristyl 97-102; 174-179; 176-181; 258-263; 375-380; 431-436; Pkc_Phospho_Site 304-306; 308-310; Tyr_Phospho_Site 62-70; DEX0291_176 Camp_Phospho_Site 13-16; Ck2_Phospho_Site 5-8; Pkc_Phospho_Site 9-11; 16-18; DEX0291_177 Myristyl 20-25; 52-57; Pkc_Phospho_Site 60-62; 86-88; DEX0291_178 Ck2_Phospho_Site 25-28; 33-36; 46-49; Pkc_Phospho_Site 15-17; 50-52; DEX0291_179 Ck2_Phospho_Site 58-61; 80-83; 84-87; Pkc_Phospho_Site 28-30; DEX0291_181 Ck2_Phospho_Site 11-14; 46-49; Pkc_Phospho_Site 2-4; 46-48; DEX0291_182 Ck2_Phospho_Site 16-19; 30-33; Myristyl 20-25; Pkc_Phospho_Site 47-49; DEX0291_183 Asn_Glycosylation 80-83; Ck2_Phospho_Site 82-85; Myristyl 26-31; 30-35; 63-68; Pkc_Phospho_Site 10-12; 82-84; DEX0291_184 Myristyl 16-21; 40-45; 44-49; Pkc_Phospho_Site 59-61; 77-79; DEX0291_185 Amidation 15-18; 88-91; Asn_Glycosylation 186-189; 396-399; Camp_Phospho_Site 476-479; Ck2_Phospho_Site 31-34; 74-77; 110-113; 198-201; 423-426; Fibrin_Ag_C_Domain 430-442; Myristyl 27-32; 40-45; 43-48; 169-174; 194-199; 362- 367; 447-452; 458-463; 470-475; Pkc_Phospho_Site 336-338; 392-394; 411-413; 474- 476; 479-481; Tyr_Phospho_Site 202-208; 288-295; DEX0291_186 Pkc_Phospho_Site 29-31; DEX0291_187 Amidation 105-108; Bzip_Basic 125-139; 126-139; Ck2_Phospho_Site 51-54; 115-118; Glycosaminoglycan 23-26; Myristyl 2-7; 37-42; 96-101; 102-107; Pkc_Phospho_Site 7- 9; 144-146; DEX0291_188 Pkc_Phospho_Site 10-12; DEX0291_189 Ck2_Phospho_Site 19-22; Pkc_Phospho_Site 3-5; 41-43; Tyr_Phospho_Site 5-13; DEX0291_190 Myristyl 49-54; Pkc_Phospho_Site 24-26; Prokar_Lipoprotein 38-48; DEX0291_191 Ck2_Phospho_Site 35-38; 95-98; Myristyl 6-11; DEX0291_192 Myristyl 22-27; Pkc_Phospho_Site 43-45; DEX0291_193 Camp_Phospho_Site 15-18; Myristyl 24-29; 27-32; Pkc_Phospho_Site 47-49; 55-57; DEX0291_194 Asn_Glycosylation 30-33; Camp_Phospho_Site 62-65; 120-123; Ck2_Phospho_Site 65- 68; 79-82; 131-134; 136-139; 138-141; 152-155; Myristyl 69-74; 73-78; 100-105; 198-203; Pkc_Phospho_Site 79-81; 133-135; 193-195; DEX0291_196 Asn_Glycosylation 32-35; Ck2_Phospho_Site 56-59; DEX0291_197 Asn_Glycosylation 36-39; Myristyl 12-17; Pkc_Phospho_Site 20-22; DEX0291_198 Ck2_Phospho_Site 73-76; Myristyl 12-17; 17-22; 66-71; Pkc_Phospho_Site 91-93; DEX0291_199 Asn_Glycosylation 125-128; Camp_Phospho_Site 70-73; Ck2_Phospho_Site 118-121; Myristyl 61-66; 131-136; Pkc_Phospho_Site 32-34; 68-70; 80-82; 89-91; 140-142; 153-155; DEX0291_200 Amidation 2-5; Asn_Glycosylation 74-77; 127-130; Ck2_Phospho_Site 76-79; 230-233; 242-245; 262-265; 423-426; 566-569; Leucine_Zipper 95-116; Myristyl 34-39; 419-424; 499-504; 536-541; Pkc_Phospho_Site 276-278; 380-382; 387-389; 442-444; 591-593; Tyr_Phospho_Site 561-568; 562-568; DEX0291_202 Myristyl 5-10; DEX0291_203 Ck2_Phospho_Site 31-34; 48-51; Myristyl 4-9; Pkc_Phospho_Site 84-86; Prokar_Lipoprotein 39-49; DEX0291_204 Asn_Glycosylation 64-67; Ck2_Phospho_Site 33-36; 166-169; 188-191; 234-237; 236-239; Pkc_Phospho_Site 66-68; 140-142; 243-245; 249-251; Tyr_Phospho_Site 124-132; DEX0291_205 Camp_Phospho_Site 22-25; Myristyl 70-75; Pkc_Phospho_Site 13-15; DEX0291_206 Ck2_Phospho_Site 66-69; 96-99; Glycosaminoglycan 50-53; Myristyl 47-52; 49-54; 53- 58; 62-67; Pkc_Phospho_Site 12-14; 132-134; 141-143; 192-194; 210-212; Prokar_Lipoprotein 159-169; DEX0291_207 Asn_Glycosylation 70-73; Ck2_Phospho_Site 15-18; 81-84; DEX0291_208 Asn_Glycosylation 75-78; Camp_Phospho_Site 84-87; Ck2_Phospho_Site 36-39; 78-81; Pkc_Phospho_Site 111-113; DEX0291_209 Asn_Glycosylation 30-33; Myristyl 5-10; Pkc_Phospho_Site 26-28; DEX0291_210 Asn_Glycosylation 56-59; 90-93; 173-176; Ck2_Phospho_Site 24-27; 58-61; 92-95; 138- 141; 148-151; 270-273; Myristyl 45-50; 49-54; 306-311; 312-317; 354-359; 397-402; 426- 431; 433-438; Peroxidase_2 252-263; Pkc_Phospho_Site 70-72; 138-140; 145-147; 163- 165; 195-197; 207-209; 252-254; 263-265; 275-277; 325-327; 359-361; 402-404; 444-446; Wd_Repeats 267-281; 351-365; DEX0291_211 Myristyl 5-10; DEX0291_212 Amidation 102-105; 521-524; Asn_Glycosylation 33-36; 62-65; 201-204; 230-233; 313- 316; 342-345; 343-346; 454-457; 536-539; Ck2_Phospho_Site 194-197; 204-207; 388- 391; 511-514; Myristyl 183-188; 220-225; Pkc_Phospho_Site 6-8; 143-145; 177-179; 286- 288; 345-347; 398-400; 404-406; 521-523; Zinc_Finger_C2h2 25-45; 53-73; 81-101; 109- 129; 137-157; 165-185; 193-213; 221-241; 249-269; 277-297; 305-325; 333-353; 361- 381; 389-409; 417-437; 445-465; 473-493; DEX0291_213 Myristyl 24-29; DEX0291_214 Pkc_Phospho_Site 9-11; DEX0291_215 Myristyl 5-10; 8-13; 11-16; DEX0291_216 Camp_Phospho_Site 18-21; Pkc_Phospho_Site 17-19; 60-62; DEX0291_217 Pkc_Phospho_Site 30-32; DEX0291_218 Asn_Glycosylation 72-75; 261-264; 370-373; 474-477; 516-519; Camp_Phospho_Site 224- 227; 366-369; Ck2_Phospho_Site 36-39; 180-183; 253-256; 333-336; 380-383; 457- 460; 778-781; Myristyl 177-182; 217-222; 266-271; 319-324; 368-373; 381-386; 384- 389; 393-398; 482-487; 575-580; 585-590; 649-654; 731-736; 732-737; Pkc_Phospho_Site 50-52; 151-153; 315-317; 475-477; 507-509; 513-515; 637-639; 653-655; 694-696; Tyr_Phospho_Site 193-200; 290-296; 681-688; DEX0291_219 Ck2_Phospho_Site 39-42; Myristyl 47-52; 48-53 Pkc_Phospho_Site 39-41; DEX0291_220 Asn_Glycosylation 20-23; Ck2_Phospho_Site 123-126; Glycosaminoglycan 72-75; Myristyl 30-35; 75-80; Pkc_Phospho_Site 123-125; Prokar_Lipoprotein 70-80; Tyr_Phospho_Site 107-114; DEX0291_221 Amidation 29-32; Asn_Glycosylation 23-26; Ck2_Phospho_Site 36-39; Pkc_Phospho_Site 24-26; 36-38; DEX0291_222 Ck2_Phospho_Site 78-81; Myristyl 34-39; 36-41; Pkc_Phospho_Site 96-98; DEX0291_223 Myristyl 27-32; 31-36; 33-38; 60-65; 64-69; 66-71; 67-72; 70-75; 77-82; 84-89; 93-98; 95-100; 98-103; Prokar_Lipoprotein 27-37; 58-68; DEX0291_224 Asn_Glycosylation 30-33; 181-184; Camp_Phospho_Site 37-40; Ck2_Phospho_Site 7- 10; Pkc_Phospho_Site 83-85; DEX0291_225 Asn_Glycosylation 24-27; Ck2_Phospho_Site 3-6; 72-75; Myristyl 20-25; Pkc_Phospho_Site 48-50; DEX0291_226 Pkc_Phospho_Site 19-21; DEX0291_227 Leucine_Zipper 10-31; Pkc_Phospho_Site 3-5; DEX0291_228 Asn_Glycosylation 182-185; Camp_Phospho_Site 27-30; Ck2_Phospho_Site 21-24; 41- 44; 78-81; 98-101; 112-115; Myristyl 53-58; 96-101; 103-108; Pkc_Phospho_Site 9-11; 58- 60; Tyr_Phospho_Site 76-82; DEX0291_229 Myristyl 13-18; DEX0291_231 Pkc_Phospho_Site 16-18; DEX0291_233 Ck2_Phospho_Site 79-82; Myristyl 22-27; 47-52; Pkc_Phospho_Site 15-17; 97-99; Prokar_Lipoprotein 42-52; DEX0291_235 Asn_Glycosylation 44-47; Myristyl 30-35; DEX0291_236 Ck2_Phospho_Site 40-43; Pkc_Phospho_Site 40-42; DEX0291_237 Ck2_Phospho_Site 13-16; Myristyl 19-24; 23-28; 54-59; Pkc_Phospho_Site 32-34; 95-97; DEX0291_238 Amidation 14-17; Pkc_Phospho_Site 14-16; DEX0291_239 Ck2_Phospho_Site 30-33; Myristyl 52-57; 53-58; 71-76; Pkc_Phospho_Site 49-51; DEX0291_240 Amidation 119-122; Camp_Phospho_Site 121-124; Ck2_Phospho_Site 124-127; 181- 184; Glycosaminoglycan 115-118; Myristyl 5-10; 13-18; 14-19; 16-21; 18-23; 19-24; 20- 25; 21-26; 22-27; 23-28; 33-38; 36-41; 37-42; 55-60; 90-95; 103-108; 105-110; 106-111; 108-113; 116-121; 136-141; 170-175; Pkc_Phospho_Site 9-11; DEX0291_241 Asn_Glycosylation 19-22; 53-56; Ck2_Phospho_Site 4-7; 80-83; Myristyl 52-57; Pkc_Phospho_Site 103-105; DEX0291_242 Leucine_Zipper 10-31; DEX0291_243 Myristyl 10-15; 57-62; DEX0291_244 Rgd 15-17; DEX0291_245 Ck2_Phospho_Site 144-147; Myristyl 5-10; 165-170; DEX0291_247 Asn_Glycosylation 73-76; 101-104; 167-170; Camp_Phospho_Site 230-233; Ck2_Phospho_Site 159-162; 194-197; Glycosaminoglycan 33-36; Leucine_Zipper 198- 219; Myristyl 2-7; 34-39; 74-79; 87-92; 112-117; 116-121; 119-124; 149-154; 164-169; 186- 191; 217-222; Pkc_Phospho_Site 43-45; 77-79; 129-131; 134-136; 171-173; DEX0291_248 Ck2_Phospho_Site 34-37; Myristyl 43-48; Pkc_Phospho_Site 58-60; Tyr_Phospho_Site 16-24; DEX0291_249 Amidation 2-5; Asn_Glycosylation 74-77; 127-130; Ck2_Phospho_Site 76-79; 230- 233; 242-245; 262-265; 423-426; 566-569; Leucine_Zipper 95-116; Myristyl 34-39; 419- 424; 499-504; 536-541; Pkc_Phospho_Site 276-278; 380-382; 387-389; 442-444; 591-593; Tyr_Phospho_Site 561-568; 562-568; DEX0291_251 Ck2_Phospho_Site 66-69; 96-99; Glycosaminoglycan 50-53; Myristyl 47-52; 49-54; 53- 58; 62-67; Pkc_Phospho_Site 12-14; 132-134; 141-143; 192-194; 210-212; Prokar_Lipoprotein 159-169; DEX0291_252 Camp_Phospho_Site 27-30; Myristyl 15-20; Pkc_Phospho_Site 5-7; DEX0291_253 Asn_Glycosylation 55-58; DEX0291_254 Pkc_Phospho_Site 9-11; DEX0291_255 Camp_Phospho_Site 20-23; Myristyl 67-72; DEX0291_256 Camp_Phospho_Site 15-18; Ck2_Phospho_Site 23-26; Pkc_Phospho_Site 18-20; 30-32; DEX0291_257 Asn_Glycosylation 2-5; 27-30; Myristyl 15-20; Pkc_Phospho_Site 4-6; DEX0291_258 Ck2_Phospho_Site 53-56; DEX0291_259 Amidation 362-365; 513-516; 968-971; Asn_Glycosylation 133-136; 144-147; 233- 236; 298-301; 478-481; 601-604; 635-638; 638-641; 830-833; Ck2_Phospho_Site 9-12; 235-238; 300-303; 343-346; 459-462; 587-590; 698-701; 706-709; 788-791; Myristyl 35-40; 53-58; 68-73; 69-74; 102-107; 211-216; 229-234; 296-301; 473-478; 728-733; 747-752; Pkc_Phospho_Site 86-88; 212-214; 235-237; 343-345; 353-355; 480-482; 617-619; 706-708; 729-731; 818-820; 925-927; Prokar_Lipoprotein 978-988; Tyr_Phospho_Site 697-704; 891-898; DEX0291_260 Ck2_Phospho_Site 17-20; 49-52; 77-80; Pkc_Phospho_Site 45-47; DEX0291_261 Pkc_Phospho_Site 5-7; 32-34; DEX0291_262 Asn_Glycosylation 76-79; Ck2_Phospho_Site 16-19; 45-48; Myristyl 6-11; 9-14; 56- 61; 58-63; Pkc_Phospho_Site 25-27; 84-86; DEX0291_264 Asn_Glycosylation 19-22; Camp_Phospho_Site 31-34; Ck2_Phospho_Site 40-43; 74-77; Myristyl 37-42; 90-95; DEX0291_267 Asn_Glycosylation 56-59; 98-101; Myristyl 66-71; DEX0291_268 Pkc_Phospho_Site 33-35; DEX0291_269 Ck2_Phospho_Site 8-11; DEX0291_270 Asn_Glycosylation 3-6; Ck2_Phospho_Site 6-9; DEX0291_271 Myristyl 10-15; DEX0291_272 Myristyl 9-14; Pkc_Phospho_Site 3-5; DEX0291_273 Ck2_Phospho_Site 29-32; Pkc_Phospho_Site 29-31; DEX0291_274 Ck2_Phospho_Site 215-218; Pkc_Phospho_Site 184-186; DEX0291_275 Myristyl 2-7; Pkc_Phospho_Site 15-17; DEX0291_276 Ck2_Phospho_Site 5-8; Pkc_Phospho_Site 21-23; 33-35; 44-46; 65-67; DEX0291_279 Myristyl 78-83; 122-127; Pkc_Phospho_Site 25-27; Prokar_Lipoprotein 49-59; DEX0291_280 Asn_Glycosylation 11-14; Camp_Phospho_Site 33-36; 34-37; Pkc_Phospho_Site 32- 34; 37-39; 51-53; DEX0291_281 Ck2_Phospho_Site 35-38; 44-47; DEX0291_282 Camp_Phospho_Site 109-112; 123-126; 161-164; Ck2_Phospho_Site 98-101; 141- 144; 150-153; 151-154; Myristyl 38-43; Pkc_Phospho_Site 23-25; 71-73; 78-80; 98- 100; 133-135; 141-143; 150-152; 155-157; 156-158; DEX0291_283 Asn_Glycosylation 2-5; Myristyl 19-24; Pkc_Phospho_Site 51-53; DEX0291_284 Ck2_Phospho_Site 5-8; 14-17; 25-28; 102-105; 137-140; 148-151; Myristyl 60-65; 91-96;

Example 6 Method of Determining Alterations in a Gene Corresponding to a Polynucleotide

[0484] RNA is isolated from individual patients or from a family of individuals that have a phenotype of interest. cDNA is then generated from these RNA samples using protocols known in the art. See, Sambrook (2001), supra. The CDNA is then used as a template for PCR, employing primers surrounding regions of interest in SEQ ID NO: 1 through 164. Suggested PCR conditions consist of 35 cycles at 95° C. for 30 seconds; 60-120 seconds at 52-58° C.; and 60-120 seconds at 70° C., using buffer solutions described in Sidransky et al, Science 252(5006): 706-9 (1991). See also Sidransky et al., Science 278(5340): 1054-9 (1997).

[0485] PCR products are then sequenced using primers labeled at their 5′ end with T4 polynucleotide kinase, employing SequiTherm Polymerase. (Epicentre Technologies). The intron-exon borders of selected exons is also determined and genomic PCR products analyzed to confirm the results. PCR products harboring suspected mutations are then cloned and sequenced to validate the results of the direct sequencing. PCR products is cloned into T-tailed vectors as described in Holton et al., Nucleic Acids Res., 19: 1156 (1991) and sequenced with T7 polymerase (United States Biochemical). Affected individuals are identified by mutations not present in unaffected individuals.

[0486] Genomic rearrangements may also be determined. Genomic clones are nick-translated with digoxigenin deoxyuridine 5′ triphosphate (Boehringer Manheim), and FISH is performed as described in Johnson et al., Methods Cell Biol. 35: 73-99 (1991). Hybridization with the labeled probe is carried out using a vast excess of human cot-1 DNA for specific hybridization to the corresponding genomic locus.

[0487] Chromosomes are counterstained with 4,6-diamino-2-phenylidole and propidium iodide, producing a combination of C-and R-bands. Aligned images for precise mapping are obtained using a triple-band filter set (Chroma Technology, Brattleboro, Vt.) in combination with a cooled charge-coupled device camera (Photometrics, Tucson, Ariz.) and variable excitation wavelength filters. Id. Image collection, analysis and chromosomal fractional length measurements are performed using the ISee Graphical Program System. (Inovision Corporation, Durham, N.C.) Chromosome alterations of the genomic region hybridized by the probe are identified as insertions, deletions, and translocations. These alterations are used as a diagnostic marker for an associated disease.

Example 7 Method of Detecting Abnormal Levels of a Polypeptide in a Biological Sample

[0488] Antibody-sandwich ELISAs are used to detect polypeptides in a sample, preferably a biological sample. Wells of a microtiter plate are coated with specific antibodies, at a final concentration of 0.2 to 10 μg/ml. The antibodies are either monoclonal or polyclonal and are produced by the method described above. The wells are blocked so that non-specific binding of the polypeptide to the well is reduced. The coated wells are then incubated for >2 hours at RT with a sample containing the polypeptide. Preferably, serial dilutions of the sample should be used to validate results. The plates are then washed three times with deionized or distilled water to remove unbound polypeptide. Next, 50 μl of specific antibody-alkaline phosphatase conjugate, at a concentration of 25-400 ng, is added and incubated for 2 hours at room temperature. The plates are again washed three times with deionized or distilled water to remove unbound conjugate. 75 μl of 4-methylumbelliferyl phosphate (MUP) or p-nitrophenyl phosphate (NPP) substrate solution are added to each well and incubated 1 hour at room temperature.

[0489] The reaction is measured by a microtiter plate reader. A standard curve is prepared, using serial dilutions of a control sample, and polypeptide concentrations are plotted on the X-axis (log scale) and fluorescence or absorbance on the Y-axis (linear scale). The concentration of the polypeptide in the sample is calculated using the standard curve.

Example 8 Formulating a Polypeptide

[0490] The secreted polypeptide composition will be formulated and dosed in a fashion consistent with good medical practice, taking into account the clinical condition of the individual patient (especially the side effects of treatment with the secreted polypeptide alone), the site of delivery, the method of administration, the scheduling of administration, and other factors known to practitioners. The “effective amount” for purposes herein is thus determined by such considerations.

[0491] As a general proposition, the total pharmaceutically effective amount of secreted polypeptide administered parenterally per dose will be in the range of about 1 μg/kg/day to 10 mg/kg/day of patient body weight, although, as noted above, this will be subject to therapeutic discretion. More preferably, this dose is at least 0.01 mg/kg/day, and most preferably for humans between about 0.01 and 1 mg/kg/day for the hormone. If given continuously, the secreted polypeptide is typically administered at a dose rate of about 1 μg/kg/hour to about 50 mg/kg/hour, either by 1-4 injections per day or by continuous subcutaneous infusions, for example, using a mini-pump. An intravenous bag solution may also be employed. The length of treatment needed to observe changes and the interval following treatment for responses to occur appears to vary depending on the desired effect.

[0492] Pharmaceutical compositions containing the secreted protein of the invention are administered orally, rectally, parenterally, intracistemally, intravaginally, intraperitoneally, topically (as by powders, ointments, gels, drops or transdermal patch), bucally, or as an oral or nasal spray. “Pharmaceutically acceptable carrier” refers to a non-toxic solid, semisolid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. The term “parenteral” as used herein refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrastemal, subcutaneous and intraarticular injection and infusion.

[0493] The secreted polypeptide is also suitably administered by sustained-release systems. Suitable examples of sustained-release compositions include semipermeable polymer matrices in the form of shaped articles, e.g., films, or microcapsules. Sustained-release matrices include polylactides (U.S. Pat. No.3,773,919, EP 58,481), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate (Sidman, U. et al., Biopolymers 22: 547-556 (1983)), poly (2-hydroxyethyl methacrylate) (R. Langer et al., J. Biomed. Mater. Res. 15: 167-277 (1981), and R. Langer, Chem. Tech. 12: 98-105 (1982)), ethylene vinyl acetate (R. Langer et al.) or poly-D-(−)-3-hydroxybutyric acid (EP 133,988). Sustained-release compositions also include liposomally entrapped polypeptides. Liposomes containing the secreted polypeptide are prepared by methods known per se: DE Epstein et al., Proc. Natl. Acad. Sci. USA 82: 3688-3692 (1985); Hwang et al., Proc. Natl. Acad. Sci. USA 77: 4030-4034 (1980); EP 52,322; EP 36,676; EP 88,046; EP 143,949; EP 142,641; Japanese Pat. Appl. 83-118008; U.S. Pat. Nos. 4,485,045 and 4,544,545; and EP 102,324. Ordinarily, the liposomes are of the small (about 200-800 Angstroms) unilamellar type in which the lipid content is greater than about 30 mol. percent cholesterol, the selected proportion being adjusted for the optimal secreted polypeptide therapy.

[0494] For parenteral administration, in one embodiment, the secreted polypeptide is formulated generally by mixing it at the desired degree of purity, in a unit dosage injectable form (solution, suspension, or emulsion), with a pharmaceutically acceptable carrier, I. e., one that is non-toxic to recipients at the dosages and concentrations employed and is compatible with other ingredients of the formulation.

[0495] For example, the formulation preferably does not include oxidizing agents and other compounds that are known to be deleterious to polypeptides. Generally, the formulations are prepared by contacting the polypeptide uniformly and intimately with liquid carriers or finely divided solid carriers or both. Then, if necessary, the product is shaped into the desired formulation. Preferably the carrier is a parenteral carrier, more preferably a solution that is isotonic with the blood of the recipient. Examples of such carrier vehicles include water, saline, Ringer's solution, and dextrose solution. Non-aqueous vehicles such as fixed oils and ethyl oleate are also useful herein, as well as liposomes.

[0496] The carrier suitably contains minor amounts of additives such as substances that enhance isotonicity and chemical stability. Such materials are non-toxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, succinate, acetic acid, and other organic acids or their salts; antioxidants such as ascorbic acid; low molecular weight (less than about ten residues) polypeptides, e.g., polyarginine or tripeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids, such as glycine, glutamic acid, aspartic acid, or arginine; monosaccharides, disaccharides, and other carbohydrates including cellulose or its derivatives, glucose, manose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; counterions such as sodium; and/or nonionic surfactants such as polysorbates, poloxamers, or PEG.

[0497] The secreted polypeptide is typically formulated in such vehicles at a concentration of about 0.1 mg/ml to 100 mg/ml, preferably 1-10 mg/ml, at a pH of about 3 to 8. It will be understood that the use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of polypeptide salts.

[0498] Any polypeptide to be used for therapeutic administration can be sterile. Sterility is readily accomplished by filtration through sterile filtration membranes (e.g., 0.2 micron membranes). Therapeutic polypeptide compositions generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.

[0499] Polypeptides ordinarily will be stored in unit or multi-dose containers, for example, sealed ampules or vials, as an aqueous solution or as a lyophilized formulation for reconstitution. As an example of a lyophilized formulation, 1 0-ml vials are filled with 5 ml of sterile-filtered 1% (w/v) aqueous polypeptide solution, and the resulting mixture is lyophilized. The infusion solution is prepared by reconstituting the lyophilized polypeptide using bacteriostatic Water-for-Injection.

[0500] The invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention. Associated with such container (s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration. In addition, the polypeptides of the present invention may be employed in conjunction with other therapeutic compounds.

Example 9 Method of Treating Decreased Levels of the Polypeptide

[0501] It will be appreciated that conditions caused by a decrease in the standard or normal expression level of a secreted protein in an individual can be treated by administering the polypeptide of the present invention, preferably in the secreted form. Thus, the invention also provides a method of treatment of an individual in need of an increased level of the polypeptide comprising administering to such an individual a pharmaceutical composition comprising an amount of the polypeptide to increase the activity level of the polypeptide in such an individual.

[0502] For example, a patient with decreased levels of a polypeptide receives a daily dose 0.1-100 μg/kg of the polypeptide for six consecutive days. Preferably, the polypeptide is in the secreted form. The exact details of the dosing scheme, based on administration and formulation, are provided above.

Example 10 Method of Treating Increased Levels of the Polypeptide

[0503] Antisense technology is used to inhibit production of a polypeptide of the present invention. This technology is one example of a method of decreasing levels of a polypeptide, preferably a secreted form, due to a variety of etiologies, such as cancer.

[0504] For example, a patient diagnosed with abnormally increased levels of a polypeptide is administered intravenously antisense polynucleotides at 0.5, 1.0, 1.5, 2.0 and 3.0 mg/kg day for 21 days. This treatment is repeated after a 7-day rest period if the treatment was well tolerated. The formulation of the antisense polynucleotide is provided above.

Example 11 Method of Treatment Using Gene Therapy

[0505] One method of gene therapy transplants fibroblasts, which are capable of expressing a polypeptide, onto a patient. Generally, fibroblasts are obtained from a subject by skin biopsy. The resulting tissue is placed in tissue-culture medium and separated into small pieces. Small chunks of the tissue are placed on a wet surface of a tissue culture flask, approximately ten pieces are placed in each flask. The flask is turned upside down, closed tight and left at room temperature over night. After 24 hours at room temperature, the flask is inverted and the chunks of tissue remain fixed to the bottom of the flask and fresh media (e.g., Ham's F12 media, with 10% FBS, penicillin and streptomycin) is added. The flasks are then incubated at 37° C. for approximately one week.

[0506] At this time, fresh media is added and subsequently changed every several days. After an additional two weeks in culture, a monolayer of fibroblasts emerge. The monolayer is trypsinized and scaled into larger flasks. pMV-7 (Kirschmeier, P. T. et al., DNA, 7: 219-25 (1988)), flanked by the long terminal repeats of the Moloney murine sarcoma virus, is digested with EcoRi and HindIII and subsequently treated with calf intestinal phosphatase. The linear vector is fractionated on agarose gel and purified, using glass beads.

[0507] The cDNA encoding a polypeptide of the present invention can be amplified using PCR primers which correspond to the 5′ and 3′ end sequences respectively as set forth in Example 1. Preferably, the 5′ primer contains an EcoRI site and the 3′ primer includes a HindIII site. Equal quantities of the Moloney murine sarcoma virus linear backbone and the amplified EcoRI and HindIII fragment are added together, in the presence of T4 DNA ligase. The resulting mixture is maintained under conditions appropriate for ligation of the two fragments. The ligation mixture is then used to transform bacteria HB 101, which are then plated onto agar containing kanamycin for the purpose of confirming that the vector has the gene of interest properly inserted.

[0508] The amphotropic pA3 17 or GP+aml2 packaging cells are grown in tissue culture to confluent density in Dulbecco's Modified Eagles Medium (DMEM) with 10% calf serum (CS), penicillin and streptomycin. The MSV vector containing the gene is then added to the media and the packaging cells transduced with the vector. The packaging cells now produce infectious viral particles containing the gene (the packaging cells are now referred to as producer cells).

[0509] Fresh media is added to the transduced producer cells, and subsequently, the media is harvested from a 10 cm plate of confluent producer cells. The spent media, containing the infectious viral particles, is filtered through a millipore filter to remove detached producer cells and this media is then used to infect fibroblast cells. Media is removed from a sub-confluent plate of fibroblasts and quickly replaced with the media from the producer cells. This media is removed and replaced with fresh media.

[0510] If the titer of virus is high, then virtually all fibroblasts will be infected and no selection is required. If the titer is very low, then it is necessary to use a retroviral vector that has a selectable marker, such as neo or his. Once the fibroblasts have been efficiently infected, the fibroblasts are analyzed to determine whether protein is produced.

[0511] The engineered fibroblasts are then transplanted onto the host, either alone or after having been grown to confluence on cytodex 3 microcarrier beads.

Example 12 Method of Treatment Using Gene Therapy-in vivo

[0512] Another aspect of the present invention is using in vivo gene therapy methods to treat disorders, diseases and conditions. The gene therapy method relates to the introduction of naked nucleic acid (DNA, RNA, and antisense DNA or RNA) sequences into an animal to increase or decrease the expression of the polypeptide.

[0513] The polynucleotide of the present invention may be operatively linked to a promoter or any other genetic elements necessary for the expression of the polypeptide by the target tissue. Such gene therapy and delivery techniques and methods are known in the art, see, for example, WO 90/11092, WO 98/11779; U.S. Pat. No. 5,693,622; 5,705,151; 5,580,859; Tabata H. et al. (1997) Cardiovasc. Res. 35 (3): 470-479, Chao J et al. (1997) Pharmacol. Res. 35 (6): 517-522, Wolff J. A. (1997) Neuromuscul. Disord. 7 (5): 314-318, Schwartz B. et al. (1996) Gene Ther. 3 (5): 405-411, Tsurumi Y. et al. (1996) Circulation 94 (12): 3281-3290 (incorporated herein by reference).

[0514] The polynucleotide constructs may be delivered by any method that delivers injectable materials to the cells of an animal, such as, injection into the interstitial space of tissues (heart, muscle, skin, lung, liver, intestine and the like). The polynucleotide constructs can be delivered in a pharmaceutically acceptable liquid or aqueous carrier.

[0515] The term “naked” polynucleotide, DNA or RNA, refers to sequences that are free from any delivery vehicle that acts to assist, promote, or facilitate entry into the cell, including viral sequences, viral particles, liposome formulations, lipofectin or precipitating agents and the like. However, the polynucleotides of the present invention may also be delivered in liposome formulations (such as those taught in Felgner P. L. et al. (1995) Ann. NY Acad. Sci. 772: 126-139 and Abdallah B. et al. (1995) Biol. Cell 85 (1): 1-7) which can be prepared by methods well known to those skilled in the art.

[0516] The polynucleotide vector constructs used in the gene therapy method are preferably constructs that will not integrate into the host genome nor will they contain sequences that allow for replication. Any strong promoter known to those skilled in the art can be used for driving the expression of DNA. Unlike other gene therapies techniques, one major advantage of introducing naked nucleic acid sequences into target cells is the transitory nature of the polynucleotide synthesis in the cells. Studies have shown that non-replicating DNA sequences can be introduced into cells to provide production of the desired polypeptide for periods of up to six months.

[0517] The polynucleotide construct can be delivered to the interstitial space of tissues within the an animal, including of muscle, skin, brain, lung, liver, spleen, bone marrow, thymus, heart, lymph, blood, bone, cartilage, pancreas, kidney, gall bladder, stomach, intestine, testis, ovary, uterus, rectum, nervous system, eye, gland, and connective tissue. Interstitial space of the tissues comprises the intercellular fluid, mucopolysaccharide matrix among the reticular fibers of organ tissues, elastic fibers in the walls of vessels or chambers, collagen fibers of fibrous tissues, or that same matrix within connective tissue ensheathing muscle cells or in the lacunae of bone. It is similarly the space occupied by the plasma of the circulation and the lymph fluid of the lymphatic channels. Delivery to the interstitial space of muscle tissue is preferred for the reasons discussed below. They may be conveniently delivered by injection into the tissues comprising these cells. They are preferably delivered to and expressed in persistent, non-dividing cells which are differentiated, although delivery and expression may be achieved in non-differentiated or less completely differentiated cells, such as, for example, stem cells of blood or skin fibroblasts. In vivo muscle cells are particularly competent in their ability to take up and express polynucleotides.

[0518] For the naked polynucleotide injection, an effective dosage amount of DNA or RNA will be in the range of from about 0.05 μg/kg body weight to about 50 mg/kg body weight. Preferably the dosage will be from about 0.005 mg/kg to about 20 mg/kg and more preferably from about 0.05 mg/kg to about 5 mg/kg. Of course, as the artisan of ordinary skill will appreciate, this dosage will vary according to the tissue site of injection. The appropriate and effective dosage of nucleic acid sequence can readily be determined by those of ordinary skill in the art and may depend on the condition being treated and the route of administration. The preferred route of administration is by the parenteral route of injection into the interstitial space of tissues. However, other parenteral routes may also be used, such as, inhalation of an aerosol formulation particularly for delivery to lungs or bronchial tissues, throat or mucous membranes of the nose. In addition, naked polynucleotide constructs can be delivered to arteries during angioplasty by the catheter used in the procedure.

[0519] The dose response effects of injected polynucleotide in muscle in vivo is determined as follows. Suitable template DNA for production of mRNA coding for polypeptide of the present invention is prepared in accordance with a standard recombinant DNA methodology. The template DNA, which may be either circular or linear, is either used as naked DNA or complexed with liposomes. The quadriceps muscles of mice are then injected with various amounts of the template DNA.

[0520] Five to six week old female and male Balb/C mice are anesthetized by intraperitoneal injection with 0.3 ml of 2.5% Avertin. A 1.5 cm incision is made on the anterior thigh, and the quadriceps muscle is directly visualized. The template DNA is injected in 0.1 ml of carrier in a 1 cc syringe through a 27 gauge needle over one minute, approximately 0.5 cm from the distal insertion site of the muscle into the knee and about 0.2 cm deep. A suture is placed over the injection site for future localization, and the skin is closed with stainless steel clips.

[0521] After an appropriate incubation time (e.g., 7 days) muscle extracts are prepared by excising the entire quadriceps. Every fifth 15 urn cross-section of the individual quadriceps muscles is histochemically stained for protein expression. A time course for protein expression may be done in a similar fashion except that quadriceps from different mice are harvested at different times. Persistence of DNA in muscle following injection may be determined by Southern blot analysis after preparing total cellular DNA and HIRT supernatants from injected and control mice.

[0522] The results of the above experimentation in mice can be use to extrapolate proper dosages and other treatment parameters in humans and other animals using naked DNA.

Example 13 Transgenic Animals

[0523] The polypeptides of the invention can also be expressed in transgenic animals. Animals of any species, including, but not limited to, mice, rats, rabbits, hamsters, guinea pigs, pigs, micro-pigs, goats, sheep, cows and non-human primates, e.g., baboons, monkeys, and chimpanzees may be used to generate transgenic animals. In a specific embodiment, techniques described herein or otherwise known in the art, are used to express polypeptides of the invention in humans, as part of a gene therapy protocol.

[0524] Any technique known in the art may be used to introduce the transgene (i.e., polynucleotides of the invention) into animals to produce the founder lines of transgenic animals. Such techniques include, but are not limited to, pronuclear microinjection (Paterson et al., Appl. Microbiol. Biotechnol. 40: 691-698 (1994); Carver et al., Biotechnology (NY) 11: 1263-1270 (1993); Wright et al., Biotechnology (NY) 9: 830-834 (1991); and Hoppe et al., U.S. Pat. No. 4,873,191 (1989)); retrovirus mediated gene transfer into germ lines (Van der Putten et al., Proc. Natl. Acad. Sci., USA 82: 6148-6152 (1985)), blastocysts or embryos; gene targeting in embryonic stem cells (Thompson et al., Cell 56: 313-321 (1989)); electroporation of cells or embryos (Lo, 1983, Mol Cell. Biol. 3: 1803-1814 (1983)); introduction of the polynucleotides of the invention using a gene gun (see, e.g., Ulmer et al., Science 259: 1745 (1993); introducing nucleic acid constructs into embryonic pleuripotent stem cells and transferring the stem cells back into the blastocyst; and sperm mediated gene transfer (Lavitrano et al., Cell 57: 717-723 (1989); etc. For a review of such techniques, see Gordon, “Transgenic Animals,” Intl. Rev. Cytol. 115: 171-229 (1989), which is incorporated by reference herein in its entirety.

[0525] Any technique known in the art may be used to produce transgenic clones containing polynucleotides of the invention, for example, nuclear transfer into enucleated oocytes of nuclei from cultured embryonic, fetal, or adult cells induced to quiescence (Campell et al., Nature 380: 64-66 (1996); Wilmut et al., Nature 385: 810813 (1997)).

[0526] The present invention provides for transgenic animals that carry the transgene in all their cells, as well as animals which carry the transgene in some, but not all their cells, I. e., mosaic animals or chimeric. The transgene may be integrated as a single transgene or as multiple copies such as in concatamers, e.g., head-to-head tandems or head-to-tail tandems. The transgene may also be selectively introduced into and activated in a particular cell type by following, for example, the teaching of Lasko et al. (Lasko et al., Proc. Natl. Acad. Sci. USA 89: 6232-6236 (1992)). The regulatory sequences required for such a cell-type specific activation will depend upon the particular cell type of interest, and will be apparent to those of skill in the art. When it is desired that the polynucleotide transgene be integrated into the chromosomal site of the endogenous gene, gene targeting is preferred. Briefly, when such a technique is to be utilized, vectors containing some nucleotide sequences homologous to the endogenous gene are designed for the purpose of integrating, via homologous recombination with chromosomal sequences, into and disrupting the function of the nucleotide sequence of the endogenous gene. The transgene may also be selectively introduced into a particular cell type, thus inactivating the endogenous gene in only that cell type, by following, for example, the teaching of Gu et al. (Gu et al., Science 265: 103-106 (1994)). The regulatory sequences required for such a cell-type specific inactivation will depend upon the particular cell type of interest, and will be apparent to those of skill in the art.

[0527] Once transgenic animals have been generated, the expression of the recombinant gene may be assayed utilizing standard techniques. Initial screening may be accomplished by Southern blot analysis or PCR techniques to analyze animal tissues to verify that integration of the transgene has taken place. The level of mRNA expression of the transgene in the tissues of the transgenic animals may also be assessed using techniques which include, but are not limited to, Northern blot analysis of tissue samples obtained from the animal, in situ hybridization analysis, and reverse transcriptase-PCR (rt-PCR). Samples of transgenic gene-expressing tissue may also be evaluated immunocytochemically or immunohistochemically using antibodies specific for the transgene product.

[0528] Once the founder animals are produced, they may be bred, inbred, outbred, or crossbred to produce colonies of the particular animal. Examples of such breeding strategies include, but are not limited to: outbreeding of founder animals with more than one integration site in order to establish separate lines; inbreeding of separate lines in order to produce compound transgenics that express the transgene at higher levels because of the effects of additive expression of each transgene; crossing of heterozygous transgenic animals to produce animals homozygous for a given integration site in order to both augment expression and eliminate the need for screening of animals by DNA analysis; crossing of separate homozygous lines to produce compound heterozygous or homozygous lines; and breeding to place the transgene on a distinct background that is appropriate for an experimental model of interest.

[0529] Transgenic animals of the invention have uses which include, but are not limited to, animal model systems useful in elaborating the biological function of polypeptides of the present invention, studying conditions and/or disorders associated with aberrant expression, and in screening for compounds effective in ameliorating such conditions and/or disorders.

Example 14 Knock-Out Animals

[0530] Endogenous gene expression can also be reduced by inactivating or “knocking out” the gene and/or its promoter using targeted homologous recombination. (E. g., see Smithies et al., Nature 317: 230-234 (1985); Thomas & Capecchi, Cell 51: 503512 (1987); Thompson et al., Cell 5: 313-321 (1989); each of which is incorporated by reference herein in its entirety). For example, a mutant, non-functional polynucleotide of the invention (or a completely unrelated DNA sequence) flanked by DNA homologous to the endogenous polynucleotide sequence (either the coding regions or regulatory regions of the gene) can be used, with or without a selectable marker and/or a negative selectable marker, to transfect cells that express polypeptides of the invention in vivo. In another embodiment, techniques known in the art are used to generate knockouts in cells that contain, but do not express the gene of interest. Insertion of the DNA construct, via targeted homologous recombination, results in inactivation of the targeted gene. Such approaches are particularly suited in research and agricultural fields where modifications to embryonic stem cells can be used to generate animal offspring with an inactive targeted gene (e.g., see Thomas & Capecchi 1987 and Thompson 1989, supra). However this approach can be routinely adapted for use in humans provided the recombinant DNA constructs are directly administered or targeted to the required site in vivo using appropriate viral vectors that will be apparent to those of skill in the art.

[0531] In further embodiments of the invention, cells that are genetically engineered to express the polypeptides of the invention, or alternatively, that are genetically engineered not to express the polypeptides of the invention (e.g., knockouts) are administered to a patient in vivo. Such cells may be obtained from the patient (I. e., animal, including human) or an MHC compatible donor and can include, but are not limited to fibroblasts, bone marrow cells, blood cells (e.g., lymphocytes), adipocytes, muscle cells, endothelial cells etc. The cells are genetically engineered in vitro using recombinant DNA techniques to introduce the coding sequence of polypeptides of the invention into the cells, or alternatively, to disrupt the coding sequence and/or endogenous regulatory sequence associated with the polypeptides of the invention, e.g., by transduction (using viral vectors, and preferably vectors that integrate the transgene into the cell genome) or transfection procedures, including, but not limited to, the use of plasmids, cosmids, YACs, naked DNA, electroporation, liposomes, etc.

[0532] The coding sequence of the polypeptides of the invention can be placed under the control of a strong constitutive or inducible promoter or promoter/enhancer to achieve expression, and preferably secretion, of the polypeptides of the invention. The engineered cells which express and preferably secrete the polypeptides of the invention can be introduced into the patient systemically, e.g., in the circulation, or intraperitoneally.

[0533] Alternatively, the cells can be incorporated into a matrix and implanted in the body, e.g., genetically engineered fibroblasts can be implanted as part of a skin graft; genetically engineered endothelial cells can be implanted as part of a lymphatic or vascular graft. (See, for example, Anderson et al. U.S. Pat. No. 5,399,349; and Mulligan & Wilson, U.S. Pat. No. 5,460,959 each of which is incorporated by reference herein in its entirety).

[0534] When the cells to be administered are non-autologous or non-MHC compatible cells, they can be administered using well known techniques which prevent the development of a host immune response against the introduced cells. For example, the cells may be introduced in an encapsulated form which, while allowing for an exchange of components with the immediate extracellular environment, does not allow the introduced cells to be recognized by the host immune system.

[0535] Transgenic and “knock-out” animals of the invention have uses which include, but are not limited to, animal model systems useful in elaborating the biological function of polypeptides of the present invention, studying conditions and/or disorders associated with aberrant expression, and in screening for compounds effective in ameliorating such conditions and/or disorders.

[0536] All patents, patent publications, and other published references mentioned herein are hereby incorporated by reference in their entireties as if each had been individually and specifically incorporated by reference herein. While preferred illustrative embodiments of the present invention are described, one skilled in the art will appreciate that the present invention can be practiced by other than the described embodiments, which are presented for purposes of illustration only and not by way of limitation. The present invention is limited only by the claims that follow.

1 284 1 338 DNA Homo sapien 1 tggatacgag cggacagccc gggcaggtac cgcatactag caaaggtaat ggtgatctag 60 caaacaaaat tggtttctag cagttagaag tgagcaggag cacttgtatt atagtattta 120 aataatcctg gttaatctct ttttaagccg agtaacccct ccagattttg cctttttatt 180 attgaggctg gctttatttt cttctacttt ttttcccgtt ttatagcagt taattatttt 240 tgtgattatt atgcaagaag cattgccctt gagttaaact gttattgttt cataagcagc 300 tattaaaata actgagcatg ttttatgaac atacacta 338 2 2446 DNA Homo sapien 2 aaggatcctt aattaaatta atcccccccc cccttttttt ttgtattctt gccagtacag 60 tatatggttt ttctacccca attacatact gggttttgta ccacatcact aaaggcccaa 120 atcattgaag atacaaaacc gtacatgcag gctggttgtc tggttagtca atggctgatt 180 tgcttcaact gtctagtatg tatgtgcagc ctgaaactgg ctccttaaaa ggaaagccgg 240 gtcagtcatc ttgaaaaaat gacatgtaaa agtaaatcga taattgtttt gagagacggt 300 acatgtttta aaggttggcc ttaagcttca gtaacattgt cattttgtga ccttttgttg 360 tcacacctgt accctaacct gacaggaatt aactactgtt tttttgtggg gcagaaagca 420 aaacctggtg ttgtgacttt tatcctaatg gttcttaggc aaggttagtg agaagaaaca 480 caaacccaga tgcatgcatt gtgcattatt ttgtagacaa gctacttttt cttctgtccc 540 tttaacaaat ttgcagcaat taccctccct ttggggtcta gagtgaaagc taatttgtgg 600 gtagatgaga ttgcagaaga atggatgtcc atggctgtga acactgcaca ctgcacatcc 660 atctccagtg ctcacactgt gcagctacca ctccctggct gcgtgccatg ctgtcgggtt 720 gcagatttgc acacataaat tcctcaggaa gagtttgcat gagcatcacc tcgcaatatt 780 ctgtactgac caaacaaggg atttgaacgt ttttcagcac aaaaggataa cttccgagtg 840 gtggtctgta cgcatactag caaaggtaat ggtgatctag caaacaaaat tggtttctgc 900 agttagaagt gagcaggagc acttgtatta tagtatttaa ataatcctgg ttaatctctt 960 tttaagccga gtaacccctc cagattttgc ctttttatta ttgaggctgg ctttattttc 1020 ttctactttt tttcccgttt tatagcagtt aattattttt gtgattatta tgcaagaagc 1080 attgcccttg agttaaactg ttattgtttc ataagcagct attaaaataa ctgagcattg 1140 ttttatgaac atacactaat ctgagatact gaaaagcttt gcaactaaaa agcaaaacaa 1200 cctacattag tcatctagcc attgtttgga tgttttgagt tgatttttta tggtgcctct 1260 tttagcttgg aatattacgt ttactttaat ccaagtctag gccttttaaa gggtccttaa 1320 aattaaagtt cagaatgtga atccctttga catctattac aggtttatag gacctttttg 1380 gttgtgatta ctgttttcaa tacgattgta taaatgaagt taactttgtc agaagttaaa 1440 atggaggtca taggagttcc tggagaaatg gctctcctgt ttctttcatt accccactga 1500 agttcacccc agtttctggc cacaagaata tgagaaagga accctgttgt tttccaaggg 1560 aaatcattcc tctctgtccc cactgttgat taactaaagt cctggacacc ttccttcctc 1620 cactggccaa gacccacctt gacccacctt gaacctcttt tcagagccga gtggcatgaa 1680 tatgtgtact gtttctgctt ctgttgatgg agtggctgtg ggagaattaa aggaaatgct 1740 aatttgagct tcattcatag gggaacctac tatatattgc atccctgctg gttggaaatt 1800 atcttcatct ctggactgca ttgtttagaa aaatgttaat ggcttacaat tctgagaact 1860 ttattgtgtg gctctggggt taagaattct gtggtttgaa aaaaaataaa tattttgtat 1920 tgattctcac gtcatttcaa tgttgtgact atgtactaaa tgcactaaga ctgggtattc 1980 tcttagaaga gtgcgttttg ttaaacagat ggcagttcac tctcattagt tctatttgtc 2040 aatattacag ccacacactt caggataact tactcaaatg tgaagtcatg ggaagctatg 2100 gctagtaaca ggaatgcttg tgaaaaattt ggagggcaag cacgagcaga ggcttttgcc 2160 actcactagc acagccagag caaggatgaa gcatgaagtc ttgttcctag tggtgcttgt 2220 atgtcagaag ccatagtgag ctcagcccgg gcgttctgca catcatctct ttaatcccag 2280 aaaaacaaat ggcggatgaa actcctattg acctgggata caagccctga ctttggctct 2340 tgatcttttg gtgggttctg aatcactcct tctgtattag ggcatatact ttcactctaa 2400 aacttgtggt aaatgaaata aatcttgtac agatgtaaaa aaaaaa 2446 3 460 DNA Homo sapien 3 acacacccaa atgtattcca agaccatact ctgtgacagc tgaaagatca aattttttgc 60 ttgctatcca gagatgagcc ttctgctcca ctgggaactt ggctctacca gctcacagac 120 ccctttggga agctgcagaa ataaaacact cccctctatg cctcactaca caagattaat 180 acacttctag tgaaagaaga attttaatgc acttgagatg aaagaagcca gatgctttcc 240 tatttatgtc ctttccaacc atttagagtg cgggggatgg aagtgtagca aggcttgacc 300 tgcaactccc aggaccctgc tggtcatgtc aatcccaagg gcagaaatat ctcttctaga 360 atccttccag ctcacctcca ctgtggctac aagtgaaagc cataagtcaa acgggagctg 420 caggaagcca cacttactgc actgtccaag aataaatcaa 460 4 594 DNA Homo sapien 4 acacacccaa atgtattcca agaccatact ctgtgacagc tgaaagatca aattttttgc 60 ttgctatcca gagatgagcc ttctgctcca ctgggaactt ggctctacca gctcacagac 120 ccctttggga agctgcagaa ataaaacact cccctctatg cctcactaca caagattaat 180 acacttctag tgaaagaaga attttaatgc acttgagatg aaagaagcca gatgctttcc 240 tatttatgtc ctttccaacc atttagagtg cgggggatgg aagtgtagca aggcttgacc 300 tgcaactccc aggaccctgc tggtcatgtc aatcccaagg gcagaaatat ctcttctaga 360 atccttccag ctcacctcca ctgtggctac aagtgaaagc cataagtcaa acgggagctg 420 caggaagcca cacttactgc actgtccaag aataaatcaa aagcttttaa tagcaagaag 480 ttaaaaataa agcagcacgt ccttaaaaat aaaatttcct acaactgaca aaataaagga 540 cgaacacgca ctggttgttt cttaaccact agtggacaag caaagggaaa aagc 594 5 283 DNA Homo sapien 5 actactaaag gcaaccggca tggactcata atatttgtgg ggacagcaaa aagactaaaa 60 gttctaagga agaaaatgcg aaccttgata gtttgaaata gttaaaaaga cagtgtagaa 120 actgcttagg cagttggatt atggactatt agatgatact tgggtctgat aatggtataa 180 ggagaataaa gtatttaggg atccaatatt acgcctgcag ctttttccaa atagttcatg 240 ggggaggggg atgtgtaagt ggttaactga agtctaacta gat 283 6 2237 DNA Homo sapien 6 tttttttttt caagaaaaaa aaatcacttt aattgaggaa cactttcagt ttgtgacaaa 60 attatgctgt gaatcaggtg ttgcaaatta tggcccactg cctgcttttg tgtaagtttt 120 attggaacac agctacattc agtccatggc tgcttttaga atacaacagt agactttaac 180 atttggaaca gggaacagaa accagagcca tacagctaat aaacttgaaa atatttacaa 240 gttgatgctt tacaaaatcc atctgctgac ccctgctctg taccattgtt ctcttctgat 300 ggtctgttta ctaaaaaata aaaacttcac aaacatgtaa aaaatagatt tgccatttaa 360 aatgtgcttt tcaagtttga ctttttagga tgcaattaat tcactaaata cagaacttaa 420 ctaaggacaa aatttaaaga tcagcattct ttcccttccc atcacgctca acttaacatg 480 aagaactgta aacatcctaa gcttacaaca aacctatcta gttagacttc agttaaccac 540 ttacacatcc ccctccccca tgaactattt ggaaaaagct gcaggcgtaa tattggatcc 600 ctaaatactt tattctcctt ataccattat cagacccaag tatcatctaa tagtccataa 660 tcaaactgcc taagcagttt ctacactgtc tttttaacta tttcaaacta tcaaggttcg 720 cattttcttc cttagaactt ttagtctttt tcttccccaa aatatttgag tccatgccag 780 ttgcctttag ttgtacccaa ataatggttt gtctatttcc taaaagtagt actcttaaat 840 ttaaatttag tgttattttt gttgtcattg ttccttcttc ctcatgtggt tgtgcaggca 900 gagcttgagc atccagattt caaaattaaa aaataaaaga taatctagtt taatatatag 960 tagttgaatc accttaagtc tagactgctg tatgagcacc cattatcttt cactatattc 1020 catcatcccc caacatatcc acagtagatg aagggcagtt tgctcaaaca ttgttttgat 1080 cctgtcatgt ctgttcagaa atgcctgtct attcagaaac ccacgtctaa taacaaaatc 1140 ttggactggt tactatcaaa acccaacaac atacagactc ctcagctagg ccctagggat 1200 atttttctac cttgatttcc aaatgttcat tgaaagaatg cttaattcta atttggaaaa 1260 aagtttttgg cttcccactt ctgctttaca cgttcatctt tcttgaaatc aaatccaatc 1320 caatctatat tctaagaacc tgctcaaatc ttggttcttc aaagctttcc ctggtatttt 1380 gcatttttgc tttgaatagt tccacgaagg ataacttctt actccttcct tcatctttct 1440 gtatcttgca tatagtaaat attaatgact tgtttgcatt ttgttatcct aacttggcta 1500 taaagaaaat cagatgtctt caccagtcgt tcaaacttca ggtctgccta cagattcata 1560 gatggctgtg gatttttata attttgtcac aaagttagtg gtaactacag gttatctcag 1620 aatatctttt ttggcgtata aatttttttc ttttcctttt ttagacagtc tctctctctg 1680 tcgcccaggc tagagtgcag tggcgtgatc ccggctcact acaacctctg cctcctgggt 1740 tcaagagatt cttagcctca gcctcccgag tagctagggt tacaggcgcg caccacctcc 1800 atgcccagct cttttgtatt tttaagtaga gacagggttt caccatgttg gtcaggctgg 1860 tctcgaactt ctgacttcag gcaaccttag ccgcctcggc ctcccaaagt gctgggatta 1920 caggcacaag ccactgcacc cagccttatt accataaatc atcttgatgc tggtacctga 1980 taagattcta tttgcttttc tttattcata gagaccacaa acagatcgca gatccaggtt 2040 tctcaaactg gagcatctgc ttaattttcc cataaaatca gtcttattct ttctgacagc 2100 tctgagactc ctccggccac gactaggtgc tgtcctggag gaaacggtgg aggacggccg 2160 cacaaaaacc aatctacctg atgaaaactc cgttcccttc tcgccagaaa cataaaatgc 2220 gatggatacg ctcgtgc 2237 7 777 DNA Homo sapien 7 tggggtcgcg gcgaggtacc tttctgtttt aaaatgttca aataatgtat tttttaaaaa 60 tgtgtaatca ttcaaggaaa cgggaaaaca agtctaaata aaaccgggtc ctaaagttta 120 ctctaggagt cattattctt cctttgcagt ctcaattcta tttactccgt aacaagtaaa 180 ctgttttatc ccttcggctg ggaaggataa tttttaccct accaagatga tgacaatgcc 240 actgcagtgc tcacccagca agaaacacat aaatatgaag cagcgtcaaa gtctttctat 300 gaagtgtatg caagaattga tttgcaatgc attaattcag gaattcagtg gagaggctcc 360 tactatacct agcagatcta aacttgagct catgataaca ctgcacaaag ctatggtaga 420 taaaagtgat aggtaatgcc aatagaacaa ttccactgac aacacaaact cctccaagaa 480 ttcttccagg cactgtgata ggatacatat ctccatagcc aactgtagtc atagagataa 540 tcacccacca gcaggcagca ggaatgctgg taaagtcctt gttggatgtt tccaggtcca 600 gcccatgttc aagaagctga gaaagtgcac taaagattgc catggcaaca caaatgaaga 660 cagtaacata accatctctc ggtagcacgt ttgagagtca accgagtgct gaagaccatt 720 aagtgacggc agctggcgta atcatgtcta gctgttctgt gtgaatgttc gtcaacc 777 8 911 DNA Homo sapien 8 ggttgacgaa cattcacaca gaacagctag acatgattac gccagctgcc gtcacttaat 60 ggtcttcagc actcggttga ctctcaaacg tgctaccgag agatggttat gttactgtct 120 tcatttgtgt tgccatggca atctttagtg cactttctca gcttcttgaa catgggctgg 180 acctggaaac atccaacaag gactttacca gcattcctgc tgcctgctgt gggtgattat 240 ctctatgact acagttggct atggagatat gtatcctatc acagtgcctg gaagaattct 300 tggaggagtt tgtgttgtca gtggaattgt tctattggca ttacctatca cttttatcta 360 ccatagcttt gtgcagtgtt atcatgagct caagtttaga tctgctaggt atagtaggag 420 cctctccact gaattcctga attaatgcat tgcaaatcaa ttcttgcata cacttcatag 480 aaagactttg atgctgcttc atatttatgt gtttcttgct gggtgagcac tgcagtggca 540 ttgtcatcat cttggtaggg taaaaattat ccttcccagc cgaagggata aaacagttta 600 cttgttatgg agtaaataga attgagactg caaaggaaga ataatgactc ctagagtaaa 660 ctttaggacc cggttttatt tagacttgtt ttcccgtttc cttgaatgat tacacatttt 720 taaaaaatac attatttgaa cattttaaaa cagaaaggta ctattttcca atgtttttcc 780 atcttatgaa ttcagaagaa gcttggaact tatagtgttt tttgtttgag agtaacattt 840 tcatttctaa atgttttata atttctcata tcaatgtcag aagtatcctg gaaacatatg 900 tcacatgcga g 911 9 445 DNA Homo sapien 9 gccgcccggg caggtacatg tgcacttaaa tgtaatagca ccaacattca ttatattatg 60 aaggggatac tttataagaa ttataaatta tttttacatg attaaataat tttggcagag 120 taagtccgca ggacttaaat aaccagtcag ccttagtatc tacatctgga ccaggaagcc 180 ttgtgttaca gacacagatt ccctgtgaag ttctccaggg tgtaaagaag gccccaggga 240 ggtgccgacg ggatgtgagg gctgcctttc agctcaggcg agcctgcaag caacagggca 300 gttgggaagg gtcacaggca caggaaggga gcagtgggca accattgatt acatcaaacc 360 aggatggttt cttcttttta aagaaacttt tgtgagtgtt tacccacccc catccacaca 420 aatatgctct ctaggaaatg tgaaa 445 10 1254 DNA Homo sapien 10 gtccgcttaa ttaaagatct tttttttttt ttttttttta ttgttaagca tatttgtata 60 ttttttacta gttatttcat acttgccctg aaagaataca cattcaaaaa gcttgaaatt 120 aggcaatgtc agtctcatca aacaaaacca gcattggaag cgaatattaa caaatatcag 180 aatgaaatta caaaatatac atctccagcc tcataaaaca tgaattttat aagcactttc 240 ataaacataa gaaaaatagc tttgacaata actatttgaa aacattatta ttaataatct 300 tgtatactgt acatgtgcac ttaaatgtaa tagcaccaac attcattata ttatgaaggg 360 gatactttat aagaattata aattattttt acatgattaa ataattttgg cagagtaagt 420 ccgcaggact taaataacca gtcagcctta gtatctacat ctggaccagg aagcctttgt 480 gttacagaca cagattccct gtgaagttct ccagggtgta aagaaggccc cagggaggtg 540 ccgacgggat gtgagggctg cctttcagct caggcgagcc tgcaagcaac agggcagttt 600 gggaagggtc acaggcacag gaagggagca gtgggcaacc attgattaca tcaaaccagg 660 atggtttctt ctttttaaag aaacttttgt tgagtgttta cccaccccca tccacacaaa 720 tatgctctct aggaaatgtg aaagtataag cttcagaaaa atgtttttct catcctttaa 780 tttctggttt tatgatcaaa tgttccgaag acactgcttc tttttgctca aaatagttga 840 cattgtcatt gcttctagtt tttcagctcc tactatgctt actatgtcca tgggtgccat 900 tgacgtcttt ggctatttat catctctaga aaagaaaaaa aaaacattaa aattttagga 960 tgtaggattc acaataaatc tcttaccaaa tcctccttaa atccctaaac tctctacctg 1020 gctctgactc caggatcacc ctttcagttc tttccatgtt tttcttcgga aaatgtagtt 1080 tcctaacctt tctacccacc cttctcgtct actcttaggt ctgcagccac agtgatagtt 1140 ctaagttgca aacctgatca tgtccttcca gtacttagtc gttgaaaaat cttcctactt 1200 cccgcagatt gaagcctgaa ctctttaata ggcatctaag gacttggacc cgga 1254 11 838 DNA Homo sapien 11 gcccgggcag gtacttaact aattgggctg aggatgaata tatcagccac agcacattaa 60 agaatgagcc aaggattgtc atggttggtc actttttaaa gtattgatta ctgcaactgg 120 agaatggaaa gtgtatattg gtgacgccaa cctcagtttc tgagcactcc tgctctgtgg 180 tgagaatcag acaaaaattc atcggggtga aaaaggcatt acctgattca cacccttgtc 240 ttgctagccc tcttccattc atttctcaca cagcacttgc tctgttaaat cctctctctg 300 tctcagacca tgcttgcccc ttcaaagggt atggttcagg ctcctttcaa gacattggag 360 tttctctctg gggaaagaga gccccctact ggtttggctt cagtctaggt ccaccatccc 420 tctcgatctg gcatcttgga gattaattta aaaggcaagc tcaccacaat gtaagcctat 480 ggtctggcca accttgcttt gggaactgtg acaccaaagc ccccaggact atctgcctct 540 ccaggagcca gatagaatga catgcctttt tcctaattgt ccacattcca cccccaagcc 600 actgccactg tgggccaagc catccatctt gcaatcttca tctaaaacag ctctcatttc 660 atgccagttt tgtcaaacct gcaccgtcac aagatattca gaagatgaaa acgttagaag 720 acacccctga attaaaagca cttactagca gggggtggat tatccaaaag tgccgtgatc 780 ggttgtacct gggtttctca ccaatggaat cagctcctgg tgaacaagca tgtgggtg 838 12 1033 DNA Homo sapien 12 atttaaggct gtacttaact aatttgggct gaggatgaat atatcagcca cagcacatta 60 aagaatgagc caaggatttg tcatggttgg tcacttttta aagtatttga ttactgcaac 120 tggagaatga aaagtgtata ttggtgacgc caacctcagt ttctgagcac tcctgctctg 180 tggtgagaat cagacaaaaa ttcatcgggg tgaaaaaaaa aaggcattac ctgattcaca 240 cccttgtctt gctagccctc ttccattcat ttctcacaca gcactttgct ctgttaaatc 300 ctctctctgt ctcagaccat tgcttgcccc ttcaaagggt atggttcagg ctcctttcaa 360 gacatttgga gtttctctct ggggaaagag agccccctac tggtttggct tcagtctagg 420 tccaccatcc ctctcgatct ggcatcttgg agattaattt aaaaggcaag ctcaccacaa 480 tgtaagccta tggtctggcc aaccttgctt ttgggaactg tgacaccaaa gcccccagga 540 ctatctgcct ctccaggagc cagatagaat gacatgcctt tttcctaatt gtccacattc 600 cacccccaac ccactgccac tgtgggccaa gccatccatc ttgcaatctt catctaaaac 660 agctctcatt tcatgccagt tttgctcaaa cctgcaccgt cacaagatat tcagaagatg 720 aaaacgtaga agacacccct gaattaaaaa cacttacata gcagtggctg gaattactcc 780 aaaacgtgcc cagtgatcgc actgtaacat gggattttct cacccaaata ggcaactcat 840 gcttcctgag tgtaatcaaa gcatgtggtg ttttggggcc atatgcacca ggtttctatt 900 ttagaaacct tcagctgtct tgcttatgta ccgtatgtaa atttattctt tttaaaaatc 960 acttttattt gattttgact tattaaatgc tttaaaagcc aaaaaaaaaa aaaaaaaaaa 1020 aaaaattggt cgg 1033 13 824 DNA Homo sapien 13 acatatgaaa gtgacctcca aggggattgg tgaatagtca taaggatctt caggctgaac 60 agactatgtc tggggaaaga acggattatg ccccattaaa taacaagttg tgttcaagag 120 tcagagcagt gagctcagag gcccttctca ctgagacagc aacatttaaa ccaaaccaga 180 ggaagtattt gtggaactca ctgcctcagt ttgggtaaag gatgagcaga caagtcaact 240 aaagaaaaaa gaaaagcaag gaggagggtt gagcaatcta gagcatggag ttgttaagtg 300 ctctctggat ttgagttgaa gagcatccat ttgagttgaa ggccgcaggg cacaatgagc 360 tctcccttct accaccagaa agtccctggt caggtctcag gtagtgcggt gtggctcagc 420 tgggttttta attagcgcat tctctatcca acatttaatt gtttgaaagc ctccatatag 480 ttagattgtg ctttgtaatt ttgttgttgt tgctctatct tattgtatat gcattgagta 540 ttaacctgaa tgttttgtta cttaaatatt aaaaaacact gttatcctac aaagaaaaaa 600 aaacaaaaca aaaaaaaaca agggtggggg taatccgtcg ggcataagct gtcccctgtg 660 tgactggggt tctccgtccc catccccatc tccgtgacac acaaaaaagg ccagacggcg 720 cacatgcact caccgaccag tacaaccaca caaggaaacg acgtaggcac accaacaacc 780 gacagcagaa agcaatacag aaaacaacaa caaccacacc tcac 824 14 1093 DNA Homo sapien 14 acctagagtg gttggaccat cagatgtttg ggcaaaactg aaagctcttt gcaaccacac 60 accttccctg agcttacatc actgcccttt tgagcagaaa gtctaaattc cttccaagac 120 agtagaattc catcccagta ccaaagccag ataggccccc taggaaactg aggtaagagc 180 agtctctaaa aactacccac agcagcattg gtgcagggga acttggccat taggttatta 240 tttgagagga aagtcctcac atcaatagta catatgaaag tgacctccaa ggggattggt 300 gaatactcat aaggatcttc aggctgaaca gactatgtct ggggaaagaa cggattatgc 360 cccattaaat aacaagttgt gttcaagagt cagagcagtg agctcagagg cccttctcac 420 tgagacagca acatttaaac caaaccagag gaagtatttg tggaactcac tgcctcagtt 480 tgggtaaagg atgagcagac aagtcaacta aagaaaaaag aaaagcaagg aggagggttg 540 agcaatctag agcatggagt ttgttaagtg ctctctggat ttgagttgaa gagcatccat 600 ttgagttgaa ggccacaggg cacaatgagc tctcccttct accaccagaa agtccctggt 660 caggtctcag gtagtgcggt gtggctcagc tgggttttta attagcgcat tctctatcca 720 acatttaatt gtttgaaagc ctccatatag ttagattgtg ctttgtaatt ttgttgttgt 780 tgctctatct tattgtatat gcattgagta ttaacctgaa tgttttgtta cttaaatatt 840 aaaaacactg ttatcctaca aaaaaaaaaa aaaaaaaaaa aaaaaaacaa gggtgggggt 900 aatccgtcgg gcataagctg tcccctgtgt gactggggtt ctccgtcccc atccccatct 960 ccgtgacaca caaaaaaggc cagacggcgc acatgcactc accgaccagt acaaccacac 1020 aaggaaacga cgtaggcaca ccaacaaccg acagcagaaa gcaatacaga aaacaacaac 1080 aaccacacct cac 1093 15 428 DNA Homo sapien 15 atgtagcgat ggcatggtca ctaatctgct cacggcgcag tgtggatgga tggtcgcggc 60 gaggtgtttt tgctgtctta atttactaaa ttgcctaatt tttagttgat ttctctacag 120 agcttacctt gtgtagctat ttctctttta ctgttgcttt ggtgtgttct tgaagtttga 180 ttgattattt ttggtcattg agttcttagt gtagtttgct agatgcatta ttaagattct 240 tttgtgtctg acacttgtgg tgagttgctt ttgaaatctg ttgagatttc catgtgaaga 300 actgataatc aggctcttga tctgcttccc taaattactt ttttagagcc caaaccccag 360 gtttagggtg agggtttgta atacaaagaa acacttccat cacttctgcc cttaaccctt 420 gcctctat 428 16 6823 DNA Homo sapien 16 aaacttggag agacgcagga caggatcccg gcggcagaag gacggagaga aaggggaccc 60 cgggacggga aaggcgcaga gcaggcgcgg gcggcggcgg cggcggggca gggcagggcg 120 ggcgtcccgg cagagggcgc gcggtcgccc tgtcgccctc cgccccgccg gggtcacagt 180 gccccctccc tcgcgcccta gccgccctgc cgggctattt ttacgcgcgg acaccggaca 240 ccggacaccg ggctggggcg gcggcggcgg cggccgaggc ggccgaggcg gggccgcacc 300 ggggccgggc gtcggggcca cacgtcggtt cgcgggtcgc cggggctgcg cgcgccatgg 360 agccgcggtg cccgccgccg tgcggctgct gcgagcggct ggtgctcaac gtggccgggc 420 tgcgcttcga gacgcgggcg cgcacgctgg gccgcttccc ggacactctg ctaggggacc 480 cagcgcgccg cggccgcttc tacgacgacg cgcgccgcga gtatttcttc gaccggcacc 540 ggcccagctt cgacgccgtg ctctactact accagtccgg tgggcggctg cggcggccgg 600 cgcacgtgcc gctcgacgtc ttcctggaag aggtggcctt ctacgggctg ggcgcggcgg 660 ccctggcacg cctgcgcgag gacgagggct gcccggtgcc gcccgagcgc cccctgcccc 720 gccgcgcctt cgcccgccag ctgtggctgc ttttcgagtt tcccgagagc tctcaggccg 780 cgcgcgtgct cgccgtagtc tccgtgctgg tcatcctcgt ctccatcgtc gtcttctgcc 840 tcgagacgct gcctgacttc cgcgacgacc gcgacggcac ggggcttgct gctgcagccg 900 cagccggccc gttccccgct ccgctgaatg gctccagcca aatgcctgga aatccacccc 960 gcctgccctt caatgacccg ttcttcgtgg tggagacgct gtgtatttgt tggttctcct 1020 ttgagctgct ggtacgcctc ctggtctgtc caagcaaggc tatcttcttc aagaacgtga 1080 tgaacctcat cgattttgtg gctatccttc cctactttgt ggcactgggc accgagctgg 1140 cccggcagcg aggggtgggc cagcaggcca tgtcactggc catcctgaga gtcatccgat 1200 tggtgcgtgt cttccgcatc ttcaagctgt cccggcactc aaagggcctg caaatcttgg 1260 gccagacgct tcgggcctcc atgcgtgagc tgggcctcct catctttttc ctcttcatcg 1320 gtgtggtcct cttttccagc gccgtctact ttgccgaagt tgaccgggtg gactcccatt 1380 tcactagcat ccctgagtcc ttctggtggg cggtagtcac catgactaca gttggctatg 1440 gagacatggc acccgtcact gtgggtggca agatagtggg ctctctgtgt gccattgcgg 1500 gcgtgctgac tatttccctg ccagtgcccg tcattgtctc caatttcagc tacttttatc 1560 accgggagac agagggcgaa gaggctggga tgttcagcca tgtggacatg cagccttgtg 1620 gcccactgga gggcaaggcc aatggggggc tggtggacgg ggaggtacct gagctaccac 1680 ctccactctg ggcaccccca gggaaacacc tggtcaccga agtgtgagga acagttgagg 1740 tctgcaggac ctcacacctc cctagaggga gggagggagg gcagggtgga gggcaaggct 1800 ggggggaggg gattgggttt aggaagagct aggttaagtc gtaacgagtg gggaaacact 1860 gagtcttgtt gggtcttggg ttgtgtggtt tggtagctcc tgtgggtacc tcctgaagca 1920 gcagcgaatg gcaatgggtt gtgttgtgtt aatgaagact caattggttc atattactct 1980 gagttgtgca aagctcatgg agccttttgg ggtagtgttg agataggttt ggtcgtatca 2040 ttttgtgagt ttcctaggtc agtgttgggt ttggttgggt tgtgagtctg ggatagtgtg 2100 gtccagctgc attgtgtagg attctgtggt ttggtgggtc ccctagggcc atgttgggtc 2160 aagttagatg gtcccccatg gcattgttga gatcgaatgt gtgtggtgtt aagtttcgtt 2220 gagacatggt ggaaattgtg tagctctgtg attcttccag gggcatgtta ttttaggttc 2280 tgtgaacttg cgagtcatgt agaaatgtga agagtccagt ggtagaattt gagctttcta 2340 ggtcacattg ggttaagttt gtatgaccaa atgaatcttg tagggttctg ttgggcttaa 2400 ctgtgtagag gtgtgtggct ggacattttt cgtggccaca gcgagttgag ttgtgttgaa 2460 ttgtacaacc atatgagcct tgtaaggcca gttcagttgg gtcatgccac tgtttgagtc 2520 tcatagggcc atgctgaatt gagttccatt gagttgtgtc actatgtgag tcctacagga 2580 agttgggttg agttggactg tgcgaacgag ttccataggg ccacatcggg ctgttttgca 2640 tttagtggta gcaccaggac ccaaaggaaa tagcagtggg gaagcatcat gtatctggga 2700 gcatgcagtg gcgagggctc tgggaggtgt gccgagctgg ctccccagct cgctgtaggg 2760 ggcgggactg gattctgtat ccatgggatt gggtgttcat ccagaggcga ctgggtaaat 2820 taggaagagg tggatgctcc tcctgtttac cccacatcca cttcattgtg ctgttcactc 2880 ccattctccc ctacagtttt atgctcagac atggaggtca gagccacaag ggaaagggga 2940 gagggggaga aaactgtact ctgtccagac atgatagagg gacagagcca aaaggataga 3000 gaaagagacc cagaaaaagg aagaggtgga aacccagaga gacagagacc caaagggaga 3060 gaaacagaga ctcagggaga gggagacaat gacctggagg gtggggtatg gcagagacgc 3120 agaagagagg aacagaaatc cagagtgggg agacagagac caagagcagg ggatagaagc 3180 cgggcgaagt ggcccatgcc tgtaatctca gcactctggg agaccgagga agggggattg 3240 attgaggcca ggagttcaag accagcctgg gcaacatggt gagaccccat ctctacaaaa 3300 aatacaaaaa ttagctgagt gtggtggcac atgcctgtga tcccagctac tcaggaagct 3360 gaggcagaaa gatcccttga ccctgagagg tagaggctgc attgagccat gattgcacca 3420 ctgcactcca gcctgggcaa cagagggagc ccccgtctca acaaacaaac aaaaagagcc 3480 agtgggggag ggagggacag agacccagag ggcagcgtca gacacccaga gttggagaca 3540 gaacaacaga gtctcaggga aagagaacca caatagaaaa aggcagaaaa ggccgggcgc 3600 ggtggctcac gcctgtaatc ccagcacttt gggaggccga ggtgggcaaa ttacgaggtc 3660 aggagatcca gaccatcctg gctaacacgg tgaaaccctg tgcctactaa aaattcaaaa 3720 aattagccgg gtgtactggc atgtgcctgt aatcctagct acttgggagg ctgaggcagg 3780 agaatcactt gaacctggga ggcggagctt gcagtgagcc aagatcacgc cactgcactc 3840 cagcctgggc gacagagcga gactctgtct caaaaataaa tgactagata aaaaaaaaaa 3900 ttgttggagt acattttccc tgcattttag agattaggac agtggtcact ttctagttgc 3960 cgtcttcaca gacaaacttg aaaggtatta aggaaaaaat tccacatagc tctgggcctt 4020 ttttgtattc tgattgccac gttaatctgt aatcgttaag tacccatgaa agaatgtgtt 4080 tcagtatcag tgcttttttg gtactttaac aagtattgta ggcacggtgg atttttttga 4140 aatacccatg tgtccaatag caagttaagg aacctagcgc atcaaatttt gttttcttca 4200 ttcatttgga accttatttt cgcaaaaaac ctagctggaa taataatgcc atattgtatt 4260 ttgcacactg ctttattttc tagaggctct gggagcaaat tacattcatc acattacctc 4320 tgctctctca agattaaagt ctttcagcaa cattctttat tgtcatcata aggaaaaact 4380 tttatcgcaa tgatagtcag ttcacattag tttagcacta tagatagtat tcagaaattg 4440 ctttctcttt ggtaaagaag ataaataggt gaattttatt gcctgtgttt tcaggcttca 4500 gaggtacctg gcaccttact caagcaaaaa caaaaaacag ctttacttca aaagcatgtg 4560 cctctggtaa attatccatc acttttgttt taaagtggtc cctccaagaa taatgtggca 4620 tacacagtgg gtttggttgt aaggcagatg taatagatga cttcaaaagc ctgctcctta 4680 ctgcactctg gacaaggccc tggtctgtat agtttggctt cctctgttaa gtcattctac 4740 aaggtgactt gccatttgaa ctttcgtaag agacctcagc agttagactg agaaaagtta 4800 gagtgctgta gttatgaagt catacatttt tgataaaata cctgtggaaa accagggatc 4860 ctctcctgtt tctctctctt gcctccccct ttccctccat tcctctgtcg cctccccctc 4920 tcctccactt tctttaagaa tcagggggta cagaataacc tacaaacaac ctcttcaaag 4980 tacccttgga aattgaagtt caatcttaag ttttttgctg tctttaattt actagaattg 5040 cctaattttt agttgatttc tctacagagc ttagcttgtg tagttatttc tcttttactg 5100 ttgctttggt gtgtcttgaa gtttgattga ttatttttgg tcattgagtt cttagtgtag 5160 tttgctagat gattattaag attcttttgt gtctgacact tgtggtgagt tgcttttgaa 5220 atctgttgag atttccatgt gagaactgat aatcaggctc ttgatctgct tccctaaatt 5280 acttttttag agcccaaacc ccaggtttag ggtgagggtt tgtaatacaa agaaacactt 5340 ccatcacttc tgcccttaac ccttgcctct attacctaag cttagtaagt agttttctta 5400 atattgtcca atgtttggtg ttatctgcat tgttttttgt ttttttaatt gtggttgttc 5460 tgacgtgtga aatttaagga aagagccatt ttttaaaaat gccgagcagg gcaatgcaag 5520 tacagccaaa tattagactt gatgtgcaat cttcggtcct ttttaatctg gggtattata 5580 ggcagtactt taaattgcaa agtcttccgg gcctattttc ctctacattt ttgtaattaa 5640 ctctgggggc ttacttgttt tggcagtact gaaatcaaag gagctggttc ttcttttctc 5700 ccaattattt tcatatgaaa gcacctacaa ttagcctgtt agtcctattc agatacatca 5760 aatatcagtg aatgctttac tattcgcaca tttaagcatc tttgttttac ataaaattag 5820 agtatgaaaa ccagtgttca attttttatc ttgttgagct tgtaaaatgc cagcaattta 5880 aaactaggac ttttcccccc ataagccaag gaggtagaat tactaataca agggttaaag 5940 aaggtagatt ttgttttcaa tatttgggta atattagaaa gattcttccc acagggaaga 6000 actagcaagt gtcccaattt tttccaaacg ttggggaggg gaaaattcac tgtatcatga 6060 aaccctaagg gtttgttgca cttcctgctt tttaggcctg gataacagta tcaccatcct 6120 tatttacaga agggtaaaac tgactcttaa tgagaaaagc tttataagtt caagggctgt 6180 aaaatatgaa ctacttaggg tcgtttgcct tccatgggaa cttggctaga cttagaaaaa 6240 gctgtttgtt gtgctaatgt aaaagtgtca tacaatttag aagatttttg aagatggtaa 6300 acttagaaga attctatgtt ctgaaatgca cacttttaga atgtttttct ttgaaaacag 6360 gctaatagtt ctttcttttt ttgacaaagt ttcagctcct ctttaaagtt attgtgtcat 6420 ttttctggtt taaatttccc ttatatttcc acctgtaatg tcagtggcaa caacatcata 6480 cttcacttac ttgttaattt actttttacc cttattctaa gagcaagttg agttgaactg 6540 aatcttcctt gtcttagtaa caatgtataa atagtggctt ttctgtacaa aaggttgtaa 6600 tgcctcctga tggatataat tttgtgattg tatttaaaag ttgaataaat cacaccagct 6660 tcctgaaaat gttcataatg catcttttgg aaaacaaata catgcctact ttgtgcatat 6720 ttgcattaac atggcaaaga ttgtatgaaa tacctgtttt tcagaaaata aaggttcagt 6780 ctcaaaagat aaaaaaaaaa aaaaaaaaaa aaaaaaggcg gtc 6823 17 984 DNA Homo sapien misc_feature (211)..(456) a, c, g or t 17 tggccctttg agatttccta tctcaccgtt acttcagttt acccttgcag ggggccaggg 60 agtcaagaat ataccgtgtt cctccagggt ttaagccggc catgccttcc cgagagcata 120 accaacttga caggggtgcc cagttacccc acaaactgaa ggaaggagat ccttcccccg 180 tccccaggag tgctctcaac cagcctcaga nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 240 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 300 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 360 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 420 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnccct aaccggccta ccacgacccc 480 actgaacagc gcatgacgcc acgagaccgg aacgacaagg cggaccaaga cagaaatcag 540 actcaaacac aacagaccaa gataaaccgg caaatccacc acagaaatcc agggcagaaa 600 aaccgacagc aacagcacaa actcgtgaga ccaaaagagc gacacaaaag ggacaaaggg 660 aaacacgaac agaaaagcca gcctatgacc agcacgacac aaccccaaac gccaccagag 720 cacccagacc gagccataga caacaacacc gacagccata acgtacggac tgctgccgac 780 aacccaaccc agcacaaata aagacgcacg gaaccccaca tgcagagcct ccactgaatg 840 gcgccacccg cacggacacg acagcaaccg ccgcaatcag accaagcact ccccaacaga 900 ccacggagag acccgcaaca agcggcagca caagacacag atcggacaac accaagaaga 960 taggagagag ccccaggtaa caac 984 18 186 DNA Homo sapien 18 ggtcgcggcg aggtacaaac gtgctgtaat tataagtctg tggtgcagtt ccattttatg 60 ctacacatta aggcttttaa ttttgtgtaa aaggaatttt tggaatagtc ttcattgaga 120 ctctttttaa tcttatactt tctaatttag aattataaga cattcaattt gaattataga 180 aaaatt 186 19 418 DNA Homo sapien 19 gatttgacta tatagccatg gtccttaatc atgctgagcg gcgcagtgtg atggatcgcc 60 cgggcaggtc acattggaat ttgaatgcag tggccaggac agcagcttga taaaccacct 120 tataggtagg taagcaagcc acgggattcc ctcggctggg ctggtgatgg ggaggggcgc 180 agtggacagg aagcgggcag ggcctgagga ccctgtactt taatgggcca caacagggct 240 cagctcctct cagaacttct gctacaatca gagttaagac cagatacatg ctacctaagg 300 ccatgaactt gacaatatct gctccagaga agccctgagc cctcgcccta ggtccctatg 360 attataaacc caatggtaag cccaagtctc acctttctaa atattctgtt tatcagtt 418 20 1811 DNA Homo sapien 20 atcccgctaa tctgggggcc caatctcccc ccaggggctc ttccaagaca ccgaggcttt 60 cgctcgtccc tgtttaacag cctgcggtgt cttttatata tacgctccct gggggcccgt 120 gtcaccacaa cgtgtggtag tgaaatagtg gcgcctctgg aggaaattcc ttgatggcgc 180 cggcctcttg tatgtgttag aagacgctct ttactatggt gtggtctagt actaattgct 240 gattcatcga tgcggccttt tttttttttt tgacggttcc tatataacgt ttatttctgg 300 aagttaaagt agatacagca atataccaaa aaaaaaaaaa aaaaaaaaaa agacaaaaaa 360 cctcacaata atataaattt ttacactatg aagtacacat tggaatttga atgcagtggc 420 caggacagca gcttataaac caccttatag gtaggtaagc aacccacggg attccctcgg 480 ctgggctggg gatggggagg gggcagtgga caggaagcgg gcagggcctg aggaccctgt 540 tctttaatgg gccacaacag ggctcagctc ctctcagaac ttttgctaca atcagagtta 600 agaccagata catgctacct aaggccatga acttgacaat atctgctcca gagaagccct 660 gaaccctcgc cctaggtccc tatgatttaa acccaatggt aagcccaagt ctcacctttc 720 taaatattct gtttatcagt taagcttatt atgtactgaa gagtgttgct ggagaagtaa 780 gagctctgca tgacacatca actgtctcca ggcaggagga ctggggcgaa ccctgttcat 840 cctagagaag gtcgtctccc ccttaattca gagaccagct aatttgattt aacaaacaga 900 attccacaga aactctgatc agctgaggca aggtggtttt gagttgccaa atccggccat 960 gcctctgagt cagaggcagc ccatccagca cgtgctaggt gttcccatac gcacaggaga 1020 ggcgagctag ccagccaagg cgggcaggcg gggaggccct ctagctgttc tgcctcacct 1080 gtggggcccc agcagggagg agtcaccagc ctcagaggga ggccaggtat acaccctcat 1140 acgagggcag actcaagttt atcagtaagc ctttgccctg catgaactga atgaagacgc 1200 cattacaagt gccactggat atcaccaaga aactggctaa gaaccatatt cctgagctca 1260 accagacacg tcgctggggc cccatagtgt gcatcatgtc caacctgtaa ctctctcccc 1320 ctcttcttcc atgaggtcct gagaccagga ttcctaaaac aaacaggatg agggaccttt 1380 agacacgcaa ggagacatgc ctctagcagg atcaggggga ctggggtcgg gagggtgggg 1440 caggaaggaa gccagaatca gaagtatccc agccctgata aggcacccac agaaacaacc 1500 tagcctctga aacagcagat caagtccagg gagaaaggga gtcaaggttg taagcaccct 1560 ctgcccagcc ttactcacta aaaggccaat acattacaaa ggaaaataag tctatttata 1620 aaaaaaagtc taaaatgctt agattctcct taaaccttcc tatttcaaca ccaaaggcca 1680 ggttgcagct tcagatgtct taagggtttg acctgaagcc cgtttcaggg attatataaa 1740 ttaccagcct gaaggaagct gaatgcttaa agcaccaagg aggctgttaa ctgaagtttc 1800 tttttttttt t 1811 21 602 DNA Homo sapien 21 cggccgccgg caggtacagg tttttttggt aatgcgattt aaaattttta aaaacatggg 60 cttcatgaaa acaccattgt tactaacttg ggcttagatg ggaatctaat gtgaatagtt 120 caagttatgg gacttgtcta aatgtgtcta tactctaaac ctgggggaag gtggtgtgga 180 acattgactt gactacagtc gaatacatgt tgggaatcat tcccaatcat aagacatcgt 240 cgtttctgta ggatgactgc atatgttcag agtagctttt tgaatttggt tcccttagct 300 ttagggatgt gatgttatag tccaaaatgt ttacaagaaa acctaagtct tcaaaagcac 360 aacttttgtt gcttaggact ttgcatcaac tgttgttcca gacctcactt caacttcttg 420 gtctctgaac tggttttagc tagcatgcat gagagacagt tttcatgtat gctagctaaa 480 accagttcag agacagtttt catgtataat gtttctgctc tgcaactgga aagtggttta 540 ctttgcacaa atgctgatga aaacttcatg actatgagac ttttcttctg tgtatcaaga 600 aa 602 22 4114 DNA Homo sapien 22 tttttttttt aattaggata atgcctttat taacgaaaat gaaacgttca ttcctccttc 60 cactcctttt cgttggtttt ttggacacag ctcacctgat cctgctaaaa acgttgtcag 120 tctgcttggg gcttccctcc ttgattgact cacgctgggg gatgtcttga aaagtattta 180 tccacttcat gggaatgagc cctccaatat cagccaacat caatcattct tacctaaaga 240 ataataagaa aaagttaata taaaagacaa gggtataaaa taaaggtttg aaaatgctag 300 tcaacttcaa aatttaaaga gtaaaaatcc agagataaag attgggggta agttacagca 360 taaaaaaata ggaagaaact tcatggtggg ggggaaatct aaaattattc ttacataaaa 420 taagtagaca cctgaattag aatgaaaact gtattttctt taaaatgtaa aagcctgact 480 ctcagtttca ccagtctgag cacaagtttg actgcaaccc aaaatatact atcccttatg 540 tgaaggtatg tgacaacgtt gacctcacca aatgagtttt aacatcagct cttttttcat 600 atgaaagcac ataccctgct ccccattcaa gtatgtcttc cattgtcagg caggctgacc 660 accttcagca ggagtcctcc aagagtgccc aactcccctt cccacagtac acaacgctgt 720 agttgttgtc ctgcaatcct ttgtatttac ctcattcttt cccatctaag tcctcactga 780 gttttaaagt tagggctgga aaagctatgc cttactggga cagcaaggaa ccaatttttt 840 tctgagggag aagacattca ccttcactat atgcctggca gggccacagt gcacaaaaca 900 aagatcagcc ttcattcaag ttccaggttt ttcttcctcc ctgaatgatt actgcaaagg 960 gtatatgaag taagagttcc ctgttgcaca tgtaccatcc ataagggata ctatatcgtt 1020 ttgcattctt ccccccattc tccacattgt cctatcttaa gtccaagccc ttttcactct 1080 caaaaaaaaa aaaaaaatat ttttttcagc actggtgttc aaaagcaacg tttttatggt 1140 taatggttta ccagcaactg ttgagatttc cagttgagtc ttaaaaattg ccaatcatta 1200 tctagcagca atgacagatg attaggagca gtcaaatcct ctgaattctt tccctaatag 1260 gcagccattt gagaactgca ctagctgaca tcactaaaac attatcagct aaagccaaaa 1320 ccaaataaag gcccagacca acatcctggc tctctaaaac ctgtccaaaa tcattaagtg 1380 aaaggcagta aatgcaggac tgtggatcat gtcactgcag ctgacaatga ttaacaatag 1440 gagacatgca acccccatta aggttaaaag tccaaaacta gtcacacgca tctctttatt 1500 ggggaaaagt gagactatta tgcattcttg gtaggtttgc aaccttgcat gaagagcacc 1560 cattgcattt ctttcatctt tcagaaagca ccggtatctg ttccaagggc ctaacagtac 1620 gaaaatacat tctggcatca cacctctgaa cccaagactg ttctcattaa aaataatttt 1680 ggtttgtaac aaaattatga aatacaatgc aagcacctcg gtatagcatt attactgaaa 1740 ccacttaatt cccagctttt tgagtttttt aaaaaaaccc actgcactaa gattcacaat 1800 tcattgctac atacaaatta aagctagtaa gaacacacta acgtcacaag tttctcattc 1860 taaagtgcaa aagcctaatc atctgaaagt gaacagggta aggcaaaatt aaccccccac 1920 cccaataaag ttcctgaagt ccatatatta tataccaagt acattctcta aaaattgtta 1980 ctgactggta agaaatagac ctgagttttt atttctaaca cccaatcact aaaccacggc 2040 agcaagcact ggccaccgat ttaatggatt acgacacagg aaaccccatc agggttctat 2100 gtaatttagt gatactcatg tcactaatat tgagcattat acttgatctg cattatattg 2160 ttgatatgca gaggctaaac tagtcatcat ttgctctttc atctatcagt agagtccaaa 2220 gttgtttgct tgaatggact acatgttaaa gtacaagtct gtccccacct tgtgaattgc 2280 ttgccaacga gcaagctttt tcttgataca cagaagaaaa gtctcatagt catgaagttt 2340 tcatcagcat ttatgcaaag taaaccactt tccagttaca gagcagaaac attatacatg 2400 aaaactgtct ctcatgcatg ctagctaaaa ccagttcaga gaccaagaag ttgaagtgag 2460 gtctggaaca acagttgatg caaagtccta agcaacaaaa gttgtgcttt tgaagactta 2520 ggttttcttg taaacatttt ggactataac atcacatccc taaagctaag ggaaccaaat 2580 tcaaaaagct actctgaaca tatgcagtca tcctacagaa acgacgatgt cttatgattg 2640 ggaatgattc ccaacatgta ttcgactgta gtcaagtcaa tgttccacac caccttcccc 2700 caggtttaga gtatagacac atttagacaa gtcccataac ttgaactatt cacattagat 2760 tcccatctaa gcccaagtta gtaacaatgg tgttttcatg aagcccatgt ttttaaaaat 2820 tttaaatcgc attacaaaaa aacctgtact tttagttcaa ctcaacttgt agaattacca 2880 agattgcata atgaaattac tgatattgcc gatctatggg caggtcagtt tgctacaata 2940 gagactaatt atcacatgct atacggtcca tgtcaaggtg ctaaaagcac cctagttccc 3000 aagtatagtt tagttccctc tcccccacac cactgatgtg ttccatgtta tcttcagtta 3060 caatgcaact aaaggaaacc acaactgagt cagatatacc aaagaatcaa gttgcacttt 3120 ttatctgaga actgcaacag cactgaattc tgcctgacaa attacagctc taaccccaca 3180 cccacacagt tttgatgtaa gctagcttta ccatacaagt gttaggtgct gcactgtaat 3240 ttcatgtcag aaatgtgatg ccagaatgcc cacggaataa aagtacatac aagtcaccaa 3300 gttagattat atgcttgtta cctacctgta tgcagtcggc aatgagaatc ttggagcaag 3360 caggaatact acatccgggt cctaatgtcc attgccattt gcggtactac gttcctcaca 3420 gttacgcact gcagaaatgc tggctaaatg cagttatgta gcaggccact actttaatag 3480 tgcataattg cagtccaaga acaccagaaa acattccgcc acaacttagt ggcttgccca 3540 agaaaagcca agtatctaaa ttttaatctg ccataatatg ccacttaaaa attgcacagg 3600 cgtaacatta caatttcccc attttttagc tgtttatatt agtggtacaa tacatctata 3660 aagagtggtg gggttaggtc tgtaatttgt caggcagaat tcagtgctgt tgcagttctc 3720 agataaaaag tgcaaacttg attctttggt atatctgact cagttgtgtg gtgtccttta 3780 gttgcattgt aactgaagat aacatggaac acatcagtgg tgtggggtta ggtctgtaat 3840 ttgtcaggca gagtgaggtt tgttgtggag ctggcagatc caaagttgga ggtgaaatgg 3900 tataaaaatg gtcaagaaat tcgacccagt accaaataca tctttgaaca caaaggatgc 3960 cagagaatcc tgtttatcaa taactgtcag atgacagatg attcagagta ttatgtgaca 4020 gccggtgatg cgaaatgttc cactgagctc ttcgtaagag agcctccatt tatggtgccg 4080 agcagctgga tagaaacccc cgctgattgt tgtt 4114 23 234 DNA Homo sapien 23 agtgtttgca acagcaccat ttgtcaaatt caaagatgct caaaaggtgt tccctacttt 60 gcatgagagg gagagctttg taacaggaaa ttgtataagg caaactctct attcattcct 120 aaggcctctg ttcattccta atgtttacat ggttctctac tctgaagggc accaacatgg 180 acctcacctt cttaacatgg aaaatcaaaa tctaaatgaa tacaattaaa agga 234 24 600 DNA Homo sapien 24 actgcattgg tggcttctcc atagggaggg ggtcctatct catagactcc aaacttcatg 60 atggcaggga ggatatctgg atttgctcac ccctgtattt tcagagcctc acacagtgcc 120 cggaacatgg taaacattta atactatctg tcaaaaacaa atgactgaaa gagcagatgg 180 aaagagccaa tcctgcattg aagagatatc catggtggcc ctaaaactac tcaaaccaga 240 tgtctcttca gcttcccact ggaaaatgga ccggtgggca aaccaccatc tcacatctca 300 gcgagagggt caatgtgcaa aagtatttaa atagcgacga ggtcccacac cccatcccag 360 gacagccccc agcatcctgc tccaacataa gcagaaaaag acaatgaggt gcaaagagct 420 tatctcctgg gatggttccc gggtggtctg cattgccaca cagcacatca tgctttgatc 480 ctgaaggaca aggccccaat aagccctatt tctcagcaca gtcttaaaat cacctggaaa 540 tcattccacc taggacccct cgtgaatcag cactgatccc aagcgacacg ggaaccccta 600 25 496 DNA Homo sapien 25 ggcaggtaca ttgtaataat aaccacaaaa taattgtata aggagaaaaa taataactga 60 cattcatggc cctctgcaag gcacagtatc tgctttctca tttggtcctt cgttggttcc 120 atcctttgaa ggtctgagag cagcaggccc attccatgaa caccaaagcc cttcctacca 180 cgccagccca gactgccatt tcccctccag aaggccagtg ttcatcatcg atagggctag 240 agaccatccc ggagtcccca tgtttcagga ctcccgaatc ttcaaatagt ccatctttaa 300 gaagggatct cctggcagct aagagggtga agctaatcgt tctacaaagt agtgcctaac 360 tgttgataag atggcagtgt gtaggaagct gtgtgttggg tcggattccc cttttcatga 420 gccattttct gtggtaggtt ccacggacat ggacaccatg gcctcatgga agcatgaaca 480 gctccaacac agggtg 496 26 1690 DNA Homo sapien 26 atgcctagca cggatgctgg tgcctcgcag ggtttacgaa tgatctgtcc cgtctccagt 60 gacgccctct caggacccac taccgaagtc attaggactc ctttgtttgc agatgacagt 120 taccgagctc agataagagg tggcaaagag tgccagtccc ccatcaaggg tggacccaac 180 aggtggacag ctcagagagg cctggatgcc ggggatgggc tctcagcaga tgtaggagga 240 gctcaagtgc tggcaacagg caagacccct ggggctgaaa ttgatttcaa gtacgccctc 300 atcgggactg ctgtgggtgt cgccatatct gctggcttcc tggccctgaa gatctgcatg 360 atcaggaggc acttatttga cgacgactct tccgacctga aaagcacacc tgggggcctc 420 agtgacacca tcccgctaaa gaagagagcc ccaaggcgaa accacaattt ctccaaaaga 480 gatgcacagg tgattgagct gtaggtgagc agtgacgtga agaggggttc tagccccgtg 540 gaaaacagcc catggttaac atctcaggat gttctgcatt caaacaccca aggctggtaa 600 tgaactttca catggactga atattggagg caaataatag aaggaataga atatacagtg 660 cctctgtcct gaaggaaaat atcatgcctc ttctggaaga aacggactgc acagaggaag 720 gattgagcaa tttagcctgc agtggaagaa ggtggacacc aaaagcttca ccctgtgttg 780 gagctgttca tgcttccatg aggccatggt gtccatgtcc gtggaaccta ccacagaaaa 840 tggctcatga aaaggggaat ccgacccaac acacagcttc ctacacactg ccatcttatc 900 aacagttagg cactactttg tagaacgatt agcttcaccc tcttagctgc caggagatcc 960 cttcttaaag atggactatg tgaagattcg ggagtcctga aacatgggga ctccgggatg 1020 gtctctagcc ctatcgatga tgaacactgg ccttctggag gggaaatggc agtctgggct 1080 ggcgtggtag gaagggcttt ggtgttcatg gaatgggcct gctgctctca gaccttcaaa 1140 ggatggaacc aacgaaggac caaatgagaa agcagatgct gtgccttgca gagggccatg 1200 aatgtcagtt attatttttc tccttataca attattttgt ggttattatt acaatgtaca 1260 tggctgttgc atagaagaca tgactggtgg aggctgagga aagccatgac attctacaat 1320 tgccatcagg ctaaggcccc gtgagcattt ctctcccttg taatattaac cctgtatttc 1380 tgggatcaca tcacggaata ttctttgcct ttccactttc caggaaatct ctcggactgg 1440 gctaccctcc ttgtgtgtga tgaaagatga gctatatttc agaacaaagt gctgtgttgt 1500 catgatttgc ctggactccc agggcgtctc ttacccaact tgataacgat gctgttcatt 1560 agcagccttt gttaactgat aaccaagagc ggtaatgtga tactcataag caattttctg 1620 tgtgtaggat aaaataaacc atcttgtatg ggaaaaaaaa aaaaaaaaaa aaaaaaaaaa 1680 aaaggcggtc 1690 27 461 DNA Homo sapien 27 gggtgataat catataggcg aatggtctct agatgctgct cgagcggcgc agtgtgatgg 60 atgcgcccgg gcaggtacca agctcccagg cccttcctct atcatggatg ctgggtgact 120 tcgggaagtc accacctctt cccaagcctg tttcccatat cacagatgtg gggccatggc 180 ctcgatgatg gtctccacag gtctttccac ctctgtgagt ccaagtcagg tcaatcagca 240 aggacccatc tctgccctgg gtcagctcct cagaaccaac ccccagcatc cctaaagcaa 300 aagcctcacc tcaagggctg ctcagaagag agcaccttca gcatgagttg ttgctggaag 360 atctaataag ctgtgtttcc tgggaagtgg tgctttactt agccctgtgg acaacttctc 420 tatgcatctg tgtgagcaga tgatcattgt attacctttt a 461 28 4043 DNA Homo sapien 28 ccgcttaatt aaagatcttt tttttttttt tttttttctc ataaacagga actttattaa 60 actacatgtt acataaaaga acatataaat ggaccattaa atacattcag tttattttaa 120 acaaatttac atagatactt atttacattt ctccattgta ttcttaaatt atttttccaa 180 gcttactacc gataaaaggt aatacaatga tcatctgctc acacagatgc atagagaagt 240 tgtccacagg gctaagtaaa gcaccacttc ccaggaaaca cagcttatta gatcttccag 300 caacaactca tgctgaaggt gctctcttct gagcagccct tgaggtgagg cttttgcttt 360 agagatgctg ggggttggtt ctgaggagct gacccagggc agagatgggt ccttgctgat 420 tgacctgact tggactcaca gaggtggaaa gacctgtgga gaccatcatc gaggccatgg 480 ccccacatct gtgatatggg aaacaggctt gggaagaggt ggtgacttcc caaagtcacc 540 cagcatccat gatagaggaa gggcctggga gcttggtacc cagggttcct ccaagaggtc 600 ccgatccctc tgctatccac aaatccacaa acttagaatc acttgcatcc attttccacc 660 accatggacc ttatgctttg aactgttttg tctacctgat taaatatata acttcttagg 720 cttcttgaga tggtgaaaag cagctcagga ttcccataag caactttgtg gagccctgga 780 aatacctact cagggctgtt tttacaagag gttttgtggt caggtgcttt actacttcag 840 ccataacgtt tacctttaaa actcagctga cttatggaag ctcagcattt ccaattcgct 900 tagatgacag gcaacagtct gcagaaggga ggttctaacg tcaaccacgt ggattcccca 960 caaacgcatc atatttgcct aaatccatct atctaccaat gtcagatcta aaatgaggtt 1020 tcactaataa gtgacctaaa attaaaaaaa acacaaaaaa gtttcttaaa aaaaaaattc 1080 caagaatttc cccgtttccc aattagtctc agaggagtcg tgaaatgggc attgggtaga 1140 aaaagtccat gttttcaact gtttcttttg aataaagcct gattccccca ctctgccccc 1200 aaacttttcc cgatgatata cattcttctg aaagcaattt catgctttta gtctgcttta 1260 aaaaacctga cttggttctt ctcaggattt aaaaaccact gtaccaagga agagatgtcc 1320 acgttaaaaa ctattattaa gagacagaga caaggagaga gagactctct ccaggccatg 1380 ttagaaaaga aggaagtgct gggagcacac aaagagagaa gaaaggctgg gagacagaat 1440 ggtttgcacc tccctgtaac cagagtgaac acaggtcata gcagccttca ctcagtttta 1500 taacagacac acgaatggag gaacatggga ttggaaagac gcacactgtc aaacagccct 1560 gatgcctttc cactaaaata tggcacttct agattccaga gaaatccagc attctaccag 1620 gggctgccac ccatctgcag ggaagcctgc cctgcaacca tgaggccctc aaggctcata 1680 ctccactgct cacaatgcgc gccctgaata catggaagca tctgatttct gtctgagtcc 1740 aactttccct cctgttccta gacagactca cacccagagt catgcacgga gaagtgggca 1800 agccagacaa tcttcaggga gacacagccc atcacaggat acccaaggct tatggggaag 1860 tccagttgcc agcaacggac cctgtgtggg caggtgaaac tctgaagcca gagaacacag 1920 gaagataaaa atatcttcat actgaggata tactgcacaa gtgtggtggc tcacacctgt 1980 aatcccagca ccttgggagg ccaaagtggg ctgatagctt gagcctagga gtttgaaact 2040 agcctgggca acataatgag accctaactc tacaaaaaaa aaaaaaatac caaaaaaaaa 2100 aaaaaaatca gctgtgttgg tagtatgtgc ctgtagtccc agctatccag gaggctgaga 2160 tgggagatca cctgagccca caacctggag tcttgatcat gctactgaac tgtagcctgg 2220 gcaacagagg atagtgagat cctgtctcaa aaaaaaaaat taattaaaaa gccaggaaac 2280 aagacttagc tctaacatct aacatagctg acaaaggagt aatttgatgt ggaattcaac 2340 ctgatattta aaagttataa aatatctata attcacaatt tggggtaaga taaagcactt 2400 gcagtttcca aagattttac aagtttacct ctcatattta tttccttatt gtgtctattt 2460 tagagcacca aatatatact aaatggaatg gacaggggat tcagatatta ttttcaaagt 2520 gacattattt gctgttggtt aatatatgct ctttttgttt ctgtcaacca aaggatggac 2580 agtgattcag aaccgtcaag acggtagtgt tgactttggc aggaaatggg atccatataa 2640 acagggattt ggaaatgttg caaccaacac agatgggaag aattactgtg gcctaccagg 2700 taacgaacag gcatgcaaaa taaaatcatt ctatttgaaa tgggattttt tttaattaaa 2760 aaacattcat tgttggaagc ctgttttagg cagttaagag gagtttcctg acaaaaatgt 2820 ggaagctaaa gataagggaa gaaaggcagt ttttagtttc ccaaaatttt atttttggtg 2880 agagatttta ttttgttttt cttttaggtg aatattggct tggaaatgat aaaattagcc 2940 agcttaccag gatgggaccc acagaacttt tgatagaaat ggaggactgg aaaggagaca 3000 aagtaaaggc tcactatgga ggattcactg tacagaatga agccaacaaa taccagatct 3060 cagtgaacaa atacagagga acagccggta atgccctcat ggatggagca tctcagctga 3120 tgggagaaaa caggaccatg accattcaca acggcatgtt cttcagcacg tatgacagag 3180 acaatgacgg ctggtatgtg tggcactctt tgctcctgct ttaaaaatca cactaatatc 3240 attactcaga atcattaaca atatttttaa tagctaccac ttcctgggca cttactgtca 3300 gccactgtcc taagctcttt atgcatcact cgaaagcatt tcaactataa ggtagacatt 3360 cttattctca ttttacagat gagatttaga gagattacgt gatttgtcca atgtcacaca 3420 actacccaga gataaaacta gaatttgagc acagttactt tctgaataat gagcatttag 3480 ataaatacct atatctctat attctaaagt gtgtgtgaaa actttcattt tcatttccag 3540 ggttctctga tactaagggt tgtaaaagct attattccag tataaagtaa caaacacagt 3600 ccctagatgg attgccacaa aggcccagtt atctctcttt cttgctatag ggcacaggag 3660 gtctttggtg tattagtgtg actctatgta tagcacccaa aggaaagact actgtgcaca 3720 cgagtgtagc agtcttttat gggtaatctg caaaacgtaa cttgaccacc gtagttctgt 3780 ttctaataac gccaaacaca ttttctttca ggttaacatc agatcccaga aaacagtgtt 3840 ctaaagaaga cggtggtgga tggtggtata atagatgtca tgcagccaat ccaaacggca 3900 gatactactg gggtggacag tacacctggg acatggcaaa gcatggcaca gatgatggtg 3960 tagtatggat gaattggaag gggtcatggt actcaatgag gaagatgagt atgaagatca 4020 ggcccttctt cccacagcaa tag 4043 29 176 DNA Homo sapien 29 ttataataac aaaaaaagtg tgaggggatg ttttcccaag cccccttctc cggtgggcgg 60 ctctcgtgtg aggacccatg gtgacagagt ctctctcatc tcctcactct gaaagcattc 120 cactggggag agtcaaccct ggctcggggc ttcctccaca cagcacacgg cccttc 176 30 1332 DNA Homo sapien misc_feature (623)..(642) 30 atcccgggaa cttgacacct cgtcccgggg cagcagcggc tctcctgcgc acgccgagtc 60 ctactccagc ggcggcggcg gccagcagaa attccgggta gatatgcctg gctcaggcag 120 tgcattcatc cccaccatca acgccatcac gaccagccag gacctgcagt ggatggtgca 180 gcccacagtg atcacctcca tgtccaaccc ataccctcgc tcgcatccct acagccccct 240 gccgggcctg gcctctgtcg ctggacacat ggccctccca agacctggcg tgatcaagac 300 cattggcacc accgtgggcc gcaggaggag agatgagcag ctgtctcctg aagaggagga 360 gaagcgtcgc atccggcggg agaggaacaa gctggctgca gccaagtgcc ggaaccgacg 420 ccgggagctg acagagaagc tgcaggcggt gaggaactct gcgtagggtg ggagcacctc 480 tgggtgggct ggagtgagag ccccgggggt cctgatcctc tctcccacag ctgtctcctt 540 acccacaaat gccctacaga tgagtcagtg gagatagagc tttccttcct ttggacacat 600 gggtcagcat tgtgttgatt gannnnnnnn nnnnnnnnnn nngtggcgtt tagcaccagc 660 cagggcccag agggaagaaa tgaacaacct tctgtggggg tgctagccac ggtttttacg 720 cagcacctga gtgttctctg ctcacagaac tgtgggggct cctgggtgag ggatgatgga 780 gggtgggagc cagggcaggt ccagacctgc cccatccagg gctgcttccc gaggttccag 840 ccactcccat gcctgccgcc atcaggagtg gcccagcctg gcctaagcac tctgggttgg 900 gccagagaga agtcttgatg gagataggtc acgtggcagc agggttgtat tttcttgggg 960 ttttctcatt tcctttatgg gcaggcgggt tccccacctc tatcatgaac tcagagctgt 1020 ggccatggta ccgcgtgctg ctcttgtgag tcactctccc gtgccgccta attgcccaga 1080 cctggggacc cgcagccctg cccttccctc tgttaagctt gacctgacca acgtcacgta 1140 actcccttca gagcctggcc ctgcaggaag ggccgtgtgc tgtgtggagg aagccccgag 1200 ccagggttga ctctccccag tggaatgctt tcagagtgag gagatgagag agactctgtc 1260 agtggtcctc acagtgactg cccaggatgg ggcttgggaa aacatcccct cacacttttt 1320 ttgttattat aa 1332 31 571 DNA Homo sapien 31 gccgcccggg caggtacctg tagtcccagc tactgaggag gctgaagcag gaggatccct 60 cgagcacaaa agtttcaggc tgtggtaagc tatgactgtg ccactgcaca ccagcctgag 120 ttacagaggg agatcccaac tcttaaaaac taaaacaaca ataaatatat acaagaatca 180 taacataaag ggattcatgc ttagaaaaaa tccataaact cccttctaaa tattgagaca 240 ctccaggctt ctttcagaca aataacttct aattattcca tatttttcaa gttattaacc 300 aagataaaga atctctcagt tagtggggaa aatgaaaatt attaagaata gaattgtctt 360 ctgactttaa aaacaattta gactttaaaa catgaactgt ttactcaggc tggtgatact 420 ctagtttgtt agtataccat acttgaagat atcatcaaga tcactatagt tgtatatatt 480 ctctattttt atatgtaatg ttaacttagt tcaagtattt tttgcttgta tcgttaactg 540 atcatcaaat acaatcctaa agatatatca g 571 32 240 DNA Homo sapien 32 ccgggcaggt acatattcta cagaaaaaaa tcaaatatgt atacaaataa gtatgcacag 60 gatttagaat cttacataaa aatgtattta acttggctgg agtgtgtgtg tgtgtttccc 120 aggttaagta aaattagaaa gccagaatca caagccacaa aaaagaaaaa ctgataaatt 180 agataccatc aaaattaaaa tctctaactg ctacaaataa taccatcaag aatgggaatt 240 33 1026 DNA Homo sapien misc_feature (883)..(883) a, c, g or t 33 aatagctcga ccgcgcgttt tgatggatga gcgacgaggt caggaggacc tgtatcacaa 60 aaaaaaagaa aagggaaaaa agaagagaaa gcagcagcat gatacctgac atgacagatg 120 tgggagaccc acagcctgca gacactgtgt ggctggaagg tggcgacggg agtggtgccg 180 gtggagtgtg gagctgtctg aaagtgacgc agcagacagt agaagcatag gtgggcgaag 240 cccaggtgac cctcaaaacg ttgcacaaga acatcaggga aaaagaacta gaatccttta 300 aggaaaatgt tcttcatgta tgagagacta aagtgatttt tctaagaaag ttcagccctt 360 ctctgactta cctggacatt tctagatact tccaaaggac cctctgggaa tccatagctt 420 cctaatctgg agatgggagg tcataaggga gacgctgtgg ggttccttga agtttcttgg 480 gttcacagag gagccccctc acttggtgtt ctcccgtgag ccagcctcca cctgccaaag 540 acactctggt cctcgtatag tgagtaatgg ggctcagggc ctctccaaca acagagagga 600 gctgatgctg tagggctgac cccgtgactt cctggagtcc tcaccctgtc cagtgctttg 660 agattcttcc cacctcccca tcctcaccag ccggatcggg cgctgtgcag tgtggtcagc 720 atggtgaaga aagtcatttc cttggtggac agtattcctc tttatctctc attacactgg 780 aaatgttatt tctgctgtat catccgtgct ccaacgtttc tagtctgtca ggctcacctt 840 ctctctggaa agaattgctt aacttgacat tccatgtgcc gcntataaaa tatattttga 900 aagaacaaaa aaaaccaaaa aaaaaaaaac ggtgggggta acctgggcca aaacgcgtcc 960 ccggggtgaa ttgttctccg ccccactcaa ccccaccaac aaaaaaataa acagacaaaa 1020 aacaaa 1026 34 1545 DNA Homo sapien 34 gccgacaatg acatcggagc cgtctcaacc acagggcatg gggaaagcat cctgaaggtg 60 aacctggcta gactcaccct gttccacata gaacaaggaa agacggtaga agaggctgcg 120 gacctatcgt tgggttatat gaagtcaagg gttaaaggtt taggtggcct catcgtggtt 180 agcaaaacag gagactgggt ggcaaagtgg acctccacct ccatgccctg ggcagccgcc 240 aaggacggca agctgcactt cggaattgat cctgacgata ctactatcac cgaccttccc 300 taagccgctg gaagattgta ttccagatgc tagcttagag gtcaagtaca gtctcctcat 360 gagacatagc ctaatcaatt agatctagaa ttggaaaaat tgtcccgtct gtcacttgtt 420 ttgttgcctt aataagcatc tgaatgtttg gttgtggggc gggttctgaa gcgatgagag 480 aaatgcccgt attaggagga ttacttgagc cctggaggtc aaagctgagg tgagccatga 540 ttactccact gcactccagc ctgggcaaca gagccaggcc ctgtatcaaa aaaaaaagaa 600 aagggaaaaa agaaagaaag cagcagcatg atcctgacat gacagatgtg ggagacccac 660 agcctgcaga cactgtgggc tggaaggtgg gaagggaggg gccggtggag gtggagctgt 720 ttgaaagtga cacagcagca gtagaagcag tggtgggcga agcccaggtg accctcagaa 780 cgttgcacaa gaacatcagg gaaaagaacc agaatccttt aaggaaaatg ttcttcatgt 840 atgagagact aaagtgattt ttctaagaaa gttcagccct tctctgactt acctggacat 900 ttctagatac ttccaaagga ccctctggga atccatagct tcctaatctg gagatgggag 960 gtcataaggg agacgctgtg gggttccttg aagtttcttg ggttcacaga ggagccccct 1020 cacttggtgt tctcccgtga gccagcctcc acctgccaaa gacactctgg tcctcgtata 1080 gtgagtaatg gggctcaggg cctctccaac aacagagagg agctgatgct gtagggctga 1140 ccccgtgact tcctgagtcc tcaccctgtc cagtgctttg agattcttcc cacctcccca 1200 tcctcaccag ccggatcggg cgctgtgcag tgtggtcagc atggtgaaga aagtcatttc 1260 ctcggtgggc agtattcctc tttatctctc attacactgg aaatgttatt tctgctgtat 1320 catccgtgct caacgtttta gtctgtcagg ctcaccttct ctctggaaag aatttgctta 1380 acttgacatt ccatgtgccg ctaataaaat atattttgaa agaaaaaaaa aaaaaaaaaa 1440 aaaaaaaacg gtgggggtaa cctgggccaa aacgcgtccc cggggtgaat tgttctccgc 1500 cccactcaac cccaccaaca aaaaaataaa cagacaaaaa acaaa 1545 35 338 DNA Homo sapien 35 tgatcactca ctataggcct ggtgctctag atcatgctcg agcggcgcag tgtgatggat 60 ggccgcccgg gcaggtactc agaatggagg ggctggaagt ggggccagtg gtcctggtag 120 tcagcctccc cttctgacac aagaattatc gtggaacagc ttgtgtgacc gatcaactgg 180 tctctccatc tttaagccat tgtcttgttg actctgttac tgcagagttt ggggaggtct 240 catggcttct cgggatccta tttcctgagc ttccctgaag ccaacttctg gccactggta 300 tgtgatgcga gcacagtgcc tcctcctgct cctccagg 338 36 1851 DNA Homo sapien 36 gccgcatatt tttttttttt tttttttttt tttttcaagg ttggaaaatc ccactttact 60 tcaagtgaag tcactgggtt gtccccatga aatatctcca caatgggtgt gctagacctt 120 tactctctgt ggcaccacca agaccccctc accctgccag agccctctga agtgtactca 180 gaatggaggg gctggaagtg gggccagtgg tcctggtagt cagcctcccc ttctgacaca 240 agaattatcg tggaacagct tgtgtgaccg atcaactggt ctctccatct ttaagccatt 300 gtcttgttga ctctgttact gcagagtttg gggaggtctc atggcttctc gcatcctatt 360 tcctgagctt ccctgaagcc aacttctggc cactggtatg tgatgcgagc acagtgcctc 420 ctcctgctcc tccaggaagc ttctgctgat tgaacgcagg ccagatggcg agatccggag 480 caaccttctt agatcaaggg aagaaagggg cacaagaggg gagtaggtaa caagataaaa 540 ggagctccct ccctgatgac tacagagcca tcgtggcagc cctgggcctc catttcagac 600 gttcatcttg cctaagccac caccatcagg gtctcagtca gtcatcattc tcatttactc 660 gggtggctgg gtgagggcgg aatactacct tccagctgtc tgagattaag cctaagccac 720 caccatcagg gtctcagtca gtcatcattc tcatttactc gggtggctgg gcgagggcgg 780 aatactacct tccagctgtc tgagattaag cagaacagca gctaaagcag taacagcagg 840 tctccttcag cagcttgcca cagggaagag ggtcccgcgt gaaccgaact caacttccac 900 ctgcgcagag gtagctacca tttgcgtaga ggtagctggg tctttaaggt tagagggaag 960 gcgcagggag ggagagacgg cgggtggggg ttgaacaaag tggagattca caaaagcaga 1020 ctagggcggg cgacgtgatc agatgacctg tgcgggcggc agcctcctgc cctcctcccc 1080 ttcgtgcgcc ggctggagcg aagagttctt ttgacagccg tgagcttccc cgccaggaac 1140 ttactggggc tgcatcaccc tagaaacgtg gctttgggct gtggaaacgc tgcctctgtg 1200 gaagtctctc ctcgcggggg tggacgggtc gctgcgcgcc cagcgttctt ctgcggttct 1260 cacagcccgc cgccgccgcc gcctcgggga cctttgcggg gaggcctcag gtcagcgccg 1320 cccttgcgat ggcgggagag cagagcggcc ccagggcctc tgagctccgg ccccggcacg 1380 tcccgccctc tcctccgctt gcgggagccg gggcgcctcg gagggaaacc ttccggacac 1440 aggccgggag aagaggggcc gtggcgccat cgcgcagctt cctggtttcg gccatgtttt 1500 tttttttttg agacggagtt tcgctctttt tgcccaggct ggagggcaat ggcgccgtct 1560 cggctccctg cagccgccgc ctcccgggtt gaagggactc tccggcctca ggccgcggtg 1620 ttcttgtaaa ttagaaccgg cctatgcgcc aagcgcgggt ctcgcggctg cggagagagg 1680 cccagcaggg ggcggggacc ccgggaggcg gggcctggcc gagctgcgca cacccgggtg 1740 gttctggcta cgggtacccg gacctgccca acgaccgttc tccattcccg acctccgcac 1800 cctacccggt ccgcagggca ccttcctcct ctctctcagg cacgtcctcg a 1851 37 409 DNA Homo sapien 37 gagagcaagt tcaagcaggg ccaggaacag gacagccggc aggagagcag gctcaacgag 60 gactttctgg gaatgctggt ccacaccagg tccctgctga aggagacact ggacatctct 120 gtgggactca ggaacaaata cgagctgctg gccctcacca ttaggagcca tgggacccga 180 ctaggtcggc tgaaaaatga ttatcttaaa gtataggtgg aaggatacaa atgctagaaa 240 gagggaatca aatcagcccc gttttggagg gtgggggaca gaagatgggg ctacatttcc 300 cccataccta ctattttttt atatcccgat ttgcactttg agaatacatc taaggtcatc 360 tttcaaaaga gaaaaattgg acacttgagt gacttgtttt tagtttgtt 409 38 2112 DNA Homo sapien 38 ttgagagcag agagatcctc aggatatctt tagccaaagg aaaagctccg cattcccacc 60 cagtccagaa attgaaatac tatcaggggg caagagcctt tctctccagc tacacactcc 120 atctcccggg agcaagggga aactccgaga ggagggcaac agagccagca tcttgccagg 180 gccccggagg aggggttccc cgctacgcct gtgccggagg agttccagtc accgagcgag 240 gggcgcaagg gtgggtgcat cctgcgctgc ggcgggcgcg ctacccagac gctggtgtgc 300 agagccacat gaagcctgct ggggactggg ggccagggag cagcaagcca gctgggactg 360 aggcggacgc tgtctcaggg agacgctgac tcgcaaagac actcccttcc ttgtgcctgg 420 gtaaaaagtc tcctcctggg gtccctggcc atcctgaata tccagaatgg tgtttctgaa 480 gttcttctgc atgagtttct tctgccacct gtgtcaaggc tacttcgatg gccccctcta 540 cccagagatg tccaatggga ctctgcacca ctacttcgtg cccgatgggg actatgagga 600 gaacgatgac cccgagaagt gccagctgct cttcagggtg agtgaccaca ggcgctgctc 660 ccagggggag gggagccagg ttggcagcct gctgagcctc accctgcggg aggagttcac 720 cgtgctgggc cgccaggtgg aggatgctgg gcgcgtgctg gagggcatca gcaaaagcat 780 ctcctacgac ctagacgggg aagagagcta tggcaagtac ctgcggcggg agtcccacca 840 gatcggggat gcctactcca actcggacaa atccctcact gagctggaga gcaagttcaa 900 gcagggccag gaacaggaca gccggcagga gagcaggctc aacgaggact ttctgggaat 960 gctggtccac accaggtccc tgctgaagga gacactggac atctctgtgg ggctcaggga 1020 caaatacgag ctgctggccc tcaccattag gagccatggg acccgactag gtcggctgaa 1080 aaatgattat cttaaagtat aggtggaagg atacaaatgc tagaaagagg gaatcaaatc 1140 agccccgttt tggagggtgg gggacagaag atggggctac atttccccca tacctactat 1200 ttttttatat cccgatttgc actttgagaa tacatctaag gtcatctttc aaaagagaaa 1260 aattggacac ttgagtgact ttgtttttag ttttgttttt gtacattatt tatgtgattg 1320 ttatggaatt gtcacctgga aagaacaatt ttaagcaatg tcatttctag atgggtttct 1380 aattctgcag agacacccgt ttcagccaca tctaaaagag cacagtttat gtggtgcgga 1440 attaaacttc cccatcctgc agattatgtg gaaataccca aagataatag tgcatagctc 1500 ctttcagcct ctagccttca ctcctgggct ccaaaagcta tcccagttgc ctgtttttca 1560 aatgaggttc aaggtgctgc tttgcatgcc tgccaaccca tggaagttgt ttcttacttc 1620 ttttctctct tatttattaa ccatggtctg agagttgttt ttgttctatg taacagtatt 1680 gccacaaaac tataggcaaa tcgtgtttgc agggagattt ctgatgcctc tgtgggtgtg 1740 tgtaagttaa agtggccaca tttaagaagg ccaagctttg tagtggttgc acagtcacac 1800 tgatatgctg atttgctctt tctcattgta tgtctatgct ttgtcatcag tgctatagta 1860 aattacaaag aaataggtag attgtatgaa catacccaca aatgcctatg atttaggtta 1920 ccaatgtatt ctttctcatt tggggttttg cttctgtctg tctgtttatt ggaaacttgt 1980 acttcaagta gggggaatcc taattctaat aactccttag ctaagtttta ttattcaggc 2040 aataaacatg ttttcatgta aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 2100 aaaaagatcg gc 2112 39 713 DNA Homo sapien misc_feature (260)..(539) a, c, g or t 39 ccgcccgggc aggtacctac ctgatgaagc tgttcatgct tccagcatca aactggacgt 60 ttactgtctg cccaaaagcc agtttccaaa aggtttgctt ccctctgttc agtggattct 120 tgactacata taggtcatat atttcaaaaa ataatgccta gctatttcta ctttgaaatc 180 atgactaaag ccaaaccaca accacagcaa agataaccta aggatttgtt taccagaaat 240 acctacaaaa aagtttgcan nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 300 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 360 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 420 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 480 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnc 540 caccctgcca aaaagtttgc catggtccgg caggcaaagt tgcaaccgga gccgttcctg 600 ggtgaaaagc ttggcggtaa tccttgtcct atccttgttc ccttgtgtgg acatttgttt 660 tccccgctcc ccaatctccc ccataccctc ccacaaaaaa aaaccaggac aac 713 40 338 DNA Homo sapien 40 ctgatttaaa gtcatagaat ttactgaaat acctacacag ctctgaatcc aacatttttg 60 catggttat tagaagaaac caaaacaact gactgaaaat gaaatgttca gtcagacagt 120 gtttgtccac atcttttttt ttttgaagtt ttgaatcatc cattcacaga aaacacttgt 180 ttatgggtat aatgcaaaac ttttgaaaca aaaaaaccta ctaaaaatgc tttcgctaaa 240 gtgattggct tttcattcat gctttgaaat aaaattatct agaaaggttg gagaagggtt 300 tgccgaacag ccatcttcct gatgtgcctt agattaga 338 41 805 DNA Homo sapien misc_feature (241)..(520) a, c, g or t 41 aatgctgctc gagcgcgcgc agttatgatg gatgtggtcg cggccgaggt ctcagtttcc 60 ctatttgtaa aatggaaata atggtagctg cctcaaacct cattacgaat tcaatgagtt 120 aaacttgaaa agacttatta cagtagctgg cacataaaga cttgatagta gtttatatgg 180 atgctatctc atattagcat atatggaatt aatagtgtat cactatactt ttttttcttt 240 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 300 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 360 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 420 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 480 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn ttactatgct atcaattcca 540 tatatggaac ggtgtcttcc ctttcagagc tctttaaagc tctgcagaag atttacatgt 600 gtttatagag ctaagagaaa tcgggccatg gaaatgtggg tgtgtaacta acaaatttaa 660 cctcttcatg ttatattaat catgcataat tctatcttca tcctctgaaa gtggcctaga 720 gcaaccatca cagtaggaag cttgggtatc atggccatag ctggtcctgg tgtgaattgt 780 ttcgtcaatc caaaaaaaaa aaaag 805 42 300 DNA Homo sapien 42 gaatgtatga tcactatagg gccatgggtt atctagatgc tgctcgagcg cgcgcagtgt 60 gatggatcgt ggtcgcggcg aggtacccct tgagcctggg caaggtgcat gacacacact 120 tggtcactgg aggaaatgat gagtagagag tgacaagcag aggaggggag ctttgggcct 180 gagtcctctg gggcacaaga gtggttgagg cttggcactt gccacctaga tttcagacaa 240 tgtgtcagga atcctggatg cccagaaaga aacctgctca gggtctggag ccccaacata 300 43 561 DNA Homo sapien 43 ggactgagaa ttcctgtggt ctcctgagat cagtttcttt ccaccagatt gtaaacaagc 60 tgtggaaagt tttagttctt agcgactcca cgacccacac tagtcaggca gaagccccca 120 tgtacaaggt accccttgag ccttggcaag gtgcatgaca cacacttggt cactggagga 180 aatgatgagt agagagtgac aagcagagga ggggagcttt gggcctgagt cctctggggc 240 acaagagtgg ttgaggcttg gcacttgcca cctagatttc agacaatgtg tcaggaatcc 300 tggatgccca gaaagaaacc tgctcagggt ctggagcccc aacataaagc ttttatttag 360 gcaatgttga gcactaatat gtggttggag ctctgcaggg ggtctccatg ggtgcactgt 420 gtagcaaagc tgtgggagaa aggccttacc cctcaaaatt ccagaattat aaatctatca 480 gccgcttgca acttcagcct ggaaaagcca tgggcattaa actccaaact gtgagagcag 540 ccatgtggct gcaccctcaa g 561 44 530 DNA Homo sapien misc_feature (102)..(182) a, c, g or t 44 gttttaaaaa gaggagctcc cctgcatgag atctcacttt ttgcctgcta ccatttatgt 60 aagatgtgac ttgctccttc ttgccttcca tcatgactgt gnnnnnnnnn nnnnnnnnnn 120 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 180 nngcccgccg cgggcgtctc cacccgcctc tccgccgccg ccccaccccc gccgccccgc 240 gcgccacgag cagatcggag cagcaggccg cgaggagcag gcgagcggcc gccagtaggc 300 gcgacgcgtg ccgcggagac gacgcccggg gcgtgcacgc cgctgaggcc gaggacagcg 360 atgcgccgcg cgaggcgcgg agcgaggagg agcggcgtgg accgccccag cggccgagga 420 cgggcgagcg gcgcggggag gcccgaaggc gaggaggagg tgcgggacgg ggggacgaga 480 agaggagaag agaggggaaa gggagggggg ggagcggaga agagggaggc 530 45 709 DNA Homo sapien 45 acaaaatagt aatgatagcc atggaagttt taccttattc tgtgagaagt gttcttaaac 60 ttattaagtg tctaaactaa ggtttagtgc ttttttaaag gaaagttgtc ccaggattca 120 tcctaaagaa agcaaaagtt aattcaactg atccaccaat ggaattagat gggtagagtt 180 gggttcttga gttttaccac cacttagttc ccgctgaatt ttgtaacttc ctgtgtttgc 240 atcctctgtt cctattctgc ccttgctctg tgtcatctca gtcatttgac ttagaaagtg 300 cccttcaaaa ggaccctgtt cactgctgca cttttcaatg aattaaaatt tatttctgtt 360 ctagctggga acacaaacaa caactcaact acaaaatcac gctctgtggg cagtatccct 420 tgcgccctta gcctttcccc cgggtgtcac tttgtcttcg cccccccatt cccccccact 480 ctcccacact ctccctcctc ccatcacttc cctccctctc tcccgctctc gctgccggcc 540 cgtcagcgcg cgtcgcgctc gcgccgtgcg gctcgcctcg ccgtctctcc ctcctctccg 600 ccgcgtcccc gccgccgcgc gtctgcccgt ccctcgtcct ccgctcccct cctccgcccg 660 ccgcctcccc ccgcccgtct gccactcgct ccctagtgcg cgcgcgccc 709 46 1808 DNA Homo sapien misc_feature (153)..(153) a, c, g or t 46 tcataagagt gaaatagtca gctgctgacg gcacctcagc cacgccacty ttactcagtt 60 cagtgggtgt gcttgcgtgg taggatgtgg tgcagccctc tctacgctct tctatttttg 120 gtatatttyc tatttaacct tcaaatagct tcnaattctt tttttcttgg actggcttca 180 ttctgaattt gtgctaaaat aatctttcat aaagagacct cagtttatag cgtaacagac 240 tacacaatgc actgatgttt tcataatgtt taagggaccc actgcaagaa ggttgctgcc 300 tccttttaat tgtattcatt tagattttga ttttccatgt taagaaggtg aggtccatgt 360 tggtgccctt cagagtagag aaccatgtaa acattaggaa tgaacagagg ccttaggaat 420 gaatagagag tttgccttat acaatttcct gttacaaagc tctccctctc atgcaaagta 480 gggaacacct tttgagcatc tttgaatttg acaaatggtg ctgttgcaaa cacttttttt 540 ttgagatgaa gtctcgcggt tgtcacccgg gctggagtgc agtggcgtga tctcggctca 600 ctgcaacttc cacctcctgg gttccagcag ttctcctgcc tcagcctccc aagtagctga 660 gattacaggc gcctgccacc ccacctggct gatttttgta attttagtag agacggggtt 720 tcaccatgtt ggccaggctg attaactcct gacctcaggt gatccacctt tctcggcctc 780 ccaaagtgct gggattacgg gtgtgagcca ccgtgcccgg cctgcaaaca cattttaatt 840 gacaacacta gggctgttgt acaaaatagt aatgatagcc atggaagttt taccttattc 900 tgtgagaagt gttcttaaac ttattaagtg tctaaactaa ggtttagtgc ttttttaaag 960 gaaagttgtc ccaggattca tcctaaagaa agcaaaagtt aattcaactg atccaccaat 1020 ggaattagat gggtagagtt gggttcttga gttttaccac cacttagttc ccactgaatt 1080 ttgtaacttc ctgtgtttgc atcctctgtt cctattctgc ccttgctctg tgtcatctca 1140 gtcatttgac ttagaaagtg cccttcaaaa ggaccctgtt cactgctgca cttttcaatg 1200 aattaaaatt tatttctgtt ctagtgggaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 1260 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 1320 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa actgagaaga gggggtgccg 1380 tgcttgtcct tctccccacg ggcgggcgca gcgcgtgcac cacccccgtg gtgttaagtt 1440 aaaagggggc agcgggcccg ctcaggcggg tgtatataag agagagagag aggggcggct 1500 tacacacaaa atagatctgg cggcagaagg aggcgaataa aaaagttgct ttcagaagtc 1560 ctcatgatac ttgggctgaa gaagacaaga acatcctttt cagaatgcgg atgtagagat 1620 aatatcaatc gaaggagcca caccacccta agtagaaaat tagtcagggt cctcagtcca 1680 tattgagcag taaaaatatt caatgattca gaagtcgtta cggatctaca acagcaagca 1740 tgatgttact tcctgccgcg gaagactgag actttgctgc tcgagtatct ataagacaaa 1800 taatatcg 1808 47 760 DNA Homo sapien 47 aatgctgctc gagccgcgcg ttatgtgatg gatgccgccg ggcaggtact gggtcccgag 60 cgtggtgggt atttgccaca ctgggtggcc agctcagcag ccccccacct ctctttattc 120 tctccaaagc tggtctttct gactatcatt gtggtagggg gaggacagat gctaaaggtg 180 gaagctgacc tggagaaaga gacacacggg gtgactgtgg caaaggacag ctggaaaaga 240 aactctatca cttcttcatt ggcaaccaca aggcacccga ggccatggca ctcccagagg 300 ctgtgcgcag tagccaagcc tctcaacctc ttctggccct gcgtcctgca gcgaagtctc 360 tgctgtaaga cagtagactc cttcgatgag gtgctcaaaa atgctacccg gggtggtggt 420 gtctggcttg cagtctggcc cagttcagag aaagttgcag agatcagggg ccaaggatgt 480 catagcccca ggttgtcctc agggtcccaa tcctagggca gggtgtgcat ggaagcaaga 540 actatggaaa cctagctcca gtctgcaggc tctgagcccc tagttcctca ctccagcggg 600 gctccctcac tgcacagaac ccaccccttc tgtgtgggca ctgctgacca cacagatgac 660 ccagacccaa agagcctggc agaagctctg tgcgttggag ctgggctccg tcctccggtc 720 tggttcaggg ggatcaggaa ggctcttttc acctgtggct 760 48 4940 DNA Homo sapien 48 tgaagttcag tagagccggc cgctgcaggc cagaaggtgg gagccagcgg gggcatcgcc 60 gcccgcgccc ctctaagtgc cgggccgcaa gctccaccgc agccgcctgc aagcagcggc 120 gcctcggccc tcgacctgcg cgcaaagcct gtgctggagc cgtcctcccg cggcggggac 180 cgggaccggg gacccaagcc aatcgaaagc tccaaccatg gccatggggc tcttccgcgt 240 gtgtctggtg gtggtgacgg ccatcatcaa ccacccgctg ctgttcccgc gggagaacgc 300 cacagtcccc gagaacgagg aggagatcat ccgcaagatg caggcgcacc aggagaagct 360 gcagctggag cagttgcgcc tggaggagga ggtggctcgg ctggcggccg aaaaggaggc 420 actggagcag gtggcggagg agggcaggca gcagaacgag acacgcgtgg cctgggacct 480 ctggagcacc ctctgcatga tcctcttcct gatgatcgag gtgtggcggc aggaccacca 540 ggaggggccc tcacctgagt gcctgggcgg tgaggaggat gagctgcctg ggctgggggg 600 cgcccccttg cagggcctca ccctgcccaa caaggccacg cttggccact tttatgagcg 660 ctgcatccgg ggggccacgg ccgatgcagc ccgtacccgg gagttcctgg aaggcttcgt 720 ggatgacttg ctggaagccc tgaggagcct ctgcaaccgg gacaccgaca tggaggtgga 780 ggacttcatt ggcgtggaca gcatgtacga gaactggcag gtggacaggc cactgctgtg 840 ccaccttttc gtgcccttca caccccccga gccctaccgc ttccacccag agctctggtg 900 ctccggccgc tcagtgcccc tggatcgcca gggctacggc cagattaagg tggtccgcgc 960 cgatggggac acattgagct gcatctgcgg caagaccaag ctcggggaag acatgctgtg 1020 tctcctgcac ggcaggaaca gcatggcgcc tccctgcggc gacatggaga acctgctgtg 1080 tgccacagat tccctgtacc tggacacgat gcaggtcatg aagtggttcc agacggccct 1140 caccagagcc tggaagggca tcgcccacaa gtacgagttc gacctggcct ttggccagct 1200 ggacagcccg gggtccctga agatcaagtt ccgttcaggg aagttcatgc ccttcaacct 1260 gattcctgtg atccagtgtg atgactcgga cctgtacttt gtctcccacc ttcccaggga 1320 gccctctgag ggcaccccag cctccagcac agactggctc ctgtcctttg ctgtctatga 1380 gcgacacttc ctcaggacga cactaaaggc actgcccgag ggcgcctgcc acctcagctg 1440 cctgcagata gcatccttcc tgctctccaa gcagagccgc ctgaccggtc ccagcgggct 1500 cagcagctac cacctgaaga cggccctact gcacctccta ctcctccggc aggccgccga 1560 ctggaaggcg gggcagctgg acgctcgtct gcacgagttg ctgtgcttcc tggagaagag 1620 cttgctccag aagaagctcc accacttctt catcggcaac cgcaaggtgc ctgaggccat 1680 gggactccct gaggccgtgc tcagggccga gcccctcaac ctcttccggc ccttcgtcct 1740 gcagcgaagc ctttaccgta agacactgga ctccttctat gagatgctca agaatgcccc 1800 agcgctcatt agcgagtatt ccctacatgt cccctcagac cagcctaccc caaaaagctg 1860 acgtctttta cagaatgtgg gatcctcgag ctaagatgag ggcatccctc acgttcacac 1920 ccctggtggc atctgccagc cctgttctgg ggacaaggcg ggctttcgtg ggagccatgc 1980 tcagcctgcc aggaagccaa gccctacagt gcagaggaaa cagaatttca acgggaagct 2040 ggtttgcttc ataccattgg gatctgctgg taaagctgtt atttgggttt agggactgat 2100 cccttgcagt ttacttctgg atcaccatga atggccaaga tggtggcaga acacgctgtg 2160 gaccctgagt tagagacaat gcaaatgttg gattgggtgt aattcttttt gaatcccaga 2220 tccagtctgt acttgaatat gagcagagga tctacaagaa tgctgacagg gaaccgtgtt 2280 aagacccagc acccctattc ccaggagctt ctggcctgac catctgcagc caaagcacta 2340 acagggacag atatgggaat gtccaccttt gatccgcatc ctgcacaata gtggtcccac 2400 catggctgcc acttttttat actatttgga gaaaagacct tgtataaatt cgaggcccga 2460 gtgactaacg tctctgtcac acggaaatgg gtacttggtg gcatagagaa acacaattag 2520 ccactttttc agctacactt ctcactcagc tgcaccctac acttctcact caggtgcacc 2580 cccttctgct gtcctttccc caacgtactg ggtcccgagc gtggtgggta tttgccacac 2640 tgggtgccag ctcagcagcc ccccacctct ctttattctc tccaaagctg gtctttctga 2700 ctatcattgt ggtaggggga ggacagatgc taaaggtgga agctgacctg gagaaagaga 2760 cacacggggt gactgtggca aaggacagct ggaaaagaaa ctctatcact tcttcattgg 2820 caaccacaag gcacctgagg ccatggcact cccagaggct gtgcgcagag ccaagcctct 2880 caacctcttc tggccctgcg tcctgcagcg aagtctctgc tgtaagacag tagactcctt 2940 cgatgaggtg ctcaaaaatg ctacccgggg tggtggtgtc tggcttgcag tctggcccag 3000 ttcagagaaa gttgcagaga tcaggggcca aggatgtcat agccccaggt tgtcctcagg 3060 gtcccaatcc tagggcaggg tgtgcatgga agcaagaact atggaaacct agctccagtc 3120 tgcaggctct gagcccctag ttcctcactc cagcggggct ccctcactgc acagaaccca 3180 ccccttctgt gtgggcactg ctgaccacac agatgaccca gacccaaaga gcctggcaga 3240 agctctgtgg ttggagctgg gctccgtctc caggtctggt tcagggggat caggaaggct 3300 cttttccacc tgtggcttca ctggcccttt gagatttcct atctcaccgt tacttcagtt 3360 acccttgcag ggggccaggg agtcaagaat ataccgtgtt cctccagggt ttaagccggc 3420 catgccttcc cgagagcata accaacttga caggggtgcc cagttacccc acaaactgaa 3480 ggaaggagat ccttccccca tccccaggag tgctctcaac cagcctcaga aagcttgaga 3540 agatggaccc tttgcccacc agggttaatt cctggtgggg cagctcggct gtgatcaggg 3600 caaccaaacc tataggaagc cttccagtgt gagctggaat tagactgaac atgtgcttgg 3660 gcctgcctct ccctagacgc agttgcgggg cactccaggg aatgaaccag ctcaagtgtg 3720 tccctaacag cagcctggag ctacccccaa tccctcacag cctgaccctc ctcattccat 3780 cagatgcatt tgtagaatcg gggcaaattt ccttatttat ttatggccca tgcctttccc 3840 cctcttcatc ctgatcccgt tttgctttga agagacccca gtaaccaaaa aacagcctcc 3900 agaagccaaa accatgcctg gatctcccat agcttctcct ttgcttccag gagaaagttc 3960 actgaaaaaa aaatatcttc tggcttcttg tgtgtacaga gacaacagaa ctcggtgggg 4020 aaacgggaat cttttctgca ccaaagctgc ttctaaagca gaaagcagtg gggctcttgg 4080 tgtttcatgc tgccttattt atattaaagg aagaattaaa tcttgcaagg agtaaaaatg 4140 gtcactgttt ggtttttaaa cttcaggaaa tctgtgaggc tcccagggca gagttgggga 4200 caggggggtg gatttcctat tgacaaagca gaagctttca ctcccttttt attcttacac 4260 tttcaggaga ctttaaaaaa taacaaaaca gaacatttct accctgtctt tgaggcaact 4320 tgtgtgctgc ccgcagggct ccagaaaggg cctttgaaag ctggctgtag ggtggattcc 4380 agcctaagac cttatttcac agagctaatg tcagcgagaa atataggagc tggaactaac 4440 aggaagcttt tgggttttaa agaaagagat tgtattttaa atagaggatt ttgagtcctc 4500 tagggcactt tggcctttcc actaaggaca accctgccct ctttccccag agtctctttc 4560 ccaaggatgc ttgactttcc ccagcaactg ctcacttgct ttgcaaaata acaagggtga 4620 aatgaataga gttggcccct aggccaagag gctggttatg ttggggaagg gccttatatc 4680 ctcaaaagct ctagcccctc tgcatgcctg gctgaagcac agccccgcgt tgagaacctg 4740 ggggtggagc tctggttcat catcaagggt gtcatccgaa tcacccagac aacctggtcc 4800 attgccccga ccccgccttg aacctacatg gtgctcagaa tccagtctgg agtggtcagg 4860 ctaggctcga tttttaaaga tttcccccaa gtgtctgatg tacccctagc tgaggaagag 4920 ctcagcttta tggtaccgac 4940 49 782 DNA Homo sapien 49 accattctga acgatgttaa agcaagtgtg gtttatttat ggcatgaacc atgtaacttg 60 aaatatgaac ttacaaggag gggcactcat taggtaacaa gttcttacac caaacttcct 120 tgatgaaata agccaaaata atcctaaaat tcattaaaaa gaacttgata aaagactcaa 180 ataaatgtta gaaagagccc ataattttag gactcctata aaattcttcc tgtttgttaa 240 tgctattaaa actcagattc aagggaaata ccagcttcca cttgagtcac tttgaaatag 300 ttaattcaac agcaccatgt tagaaatata ttggcagcca agactctgaa ctctgcagaa 360 acatttgttt cacccagact tcaaactcta gccctgacta tgatgcccct gtgtgcattt 420 acaataaaga ctccaacgga gggagcctgt tggtgttaaa ttgtttacat ttctttatac 480 aaataatgtg ctttcagtgc cttagttaca gctccctttc tgtttcttgt tccaaaggga 540 ttctgtagta tgtaggtgtg ttttcttagg taaagtctct tattgctact gaaagggaaa 600 tggtctctaa acactggtca ctgtagcagg taaacactac tctaacgtgg gagaaatgag 660 cctccatgct gaggtagggg gtgccctaaa gcctgttatt tatgctgtga aaacgaaatg 720 ggtttgctac ctgataagct gggggatcca tggcctagct gttcctgggt gaatgtttcg 780 ca 782 50 2675 DNA Homo sapien 50 ggtttatcct aaattactca accccttgta gccttgacaa attttacctt aaaaccaaaa 60 tgaaacacaa aaattaatcc ttaataatga tagcaagtga tctttctttt tagttttagc 120 cttccttttt caatagtaat atttaaaccc actcttgacc aattgtttgc ccaaatattc 180 ttgtcatttg gagtcagtgg aaaatccagc acaccaagca ccagtcttct tctgaggcaa 240 aagaaaagtg ttgtcatttt cactctgttg gagctgcaca ctttttttct ttttcttttt 300 ttttttttgt cgtgtaagaa ggatgctggt cagagctgca gaaaatatga ggcaattaaa 360 agtctttagc tgttagcaaa cctgttagtt ttacttctgc attgaaccag cctcagaagc 420 tacttactgc tttatgtact ctttgggcat taatgccttc tctgtaatta tatctcgttt 480 ttgcttgaca gtgacctagc cagtaattgc atcgtgcatt gccatgaaag gtaaacacat 540 tgtgaactga acttaccaag cagattctgt aagaaagcgc tggttgaggc tgaacactgt 600 tgacacatca tttttattgg aagagtatta actggtgcct cttctgaaac acaccaaccc 660 atattcctct gctcccccaa agctgtttct gatcctgctg ggagcaacta actagttatt 720 atgcacatct gctccagacc cagctcttta acttcacggt tttacagctt gttttttctt 780 tttcttttct tttctttttt ttttttaaaa aagcaccttt ttttgttgtt tccccttaat 840 aaaagaggtt tctaatttat gtttctctaa gatttccttt ggttgtattt agaaacacaa 900 atagttttat aatcaggatt gcatttgtgc tgggtaaaag aggagagctg tgctttctac 960 cccaaagttg ttggtaatgg agccggtctg cccttcctac aaactcaaga ggctcattgt 1020 tcaaggtgta acaacattta attgcatgtc ctctaacgct ttgaaacctt tagagggaag 1080 atcctcattt tttacaattt tgttcctttt catcatagaa aacatgttta agataaaata 1140 caaactttac ctaccccaaa ttcataaagt acatttagtg ctgtatagca ctaaaactta 1200 gagatacaga cactgtactt actttttaag aattagagac agtaactcca aaaataattg 1260 tccttttttc tttctttttt tttttttaca ataaggctct tgaaaattgt cattacttgt 1320 gttttcctat acattcatct gtgtgaaagc ctttttcttc tttgatttaa aaaaattata 1380 cagttaatgg tttagaactt agaactactt agaattaatg ctaaagtgtc aggaagaaat 1440 taatttagct tcaataattg tgactggcct caggaattct cccttccaca cctgcccacc 1500 tcacctcacc tcacctcacc gcaccgcacc gcaccgcacc gcaccgcacc agagccagag 1560 cagctgcttg tctgcagcag gacacggttc ctacatacgt ttcagttctt tcatggtaag 1620 ctcaatggac tttgaattgt ttacagtgct gtatgtccaa ttgttaaatg taccattctg 1680 aacgatgtta aagcaagtgt ggtttattta tggcatgaac catgtaactt gaaatatgaa 1740 cttacaagga ggggcactca ttaggtaaca agttcttaca ccaaacttcc ttgatgaaat 1800 aagccaaaat aatcctaaaa ttcattagaa gaacttgata aaagactcaa ataaatgtta 1860 gaaagagccc gtaattttag gactcctata aaattcttcc ttgtttgtta atgctattaa 1920 aactcagatt caagggaaat accagcttcc acttgagtca ctttgaaata gttaattcaa 1980 cagcaccatg ttagaaatat attggcagcc aagactctga actctgcaga aacatttgtt 2040 tcacccagac ttcaaactct agccctgact atgatgcccc tgtgtgcatt tacaataaag 2100 actccaacgg agggagcctg ttggtgttaa attgtttaca tttctttata caaataatgt 2160 gctttcagtg ccttagttac agctcccttt ctgtttcttg ttccaaggat tctgtagtat 2220 gtagtgtgtt tcttaggtaa agtctctttt tgctactgaa agggaaatgg tctctaaaca 2280 ctggtcactg tagcaggtaa acactactct aacgtggaga aatgagcttc atgctgaggt 2340 agtggttgcc ttagagctgt tatttatgct gtagaaaacg aaaatggttt tgctacctga 2400 taagcttcag attagatata gccctaaagt tatcctgtac ctgcattaaa ttttcatttt 2460 agaagagaat cttggttttg gtaattcatt tttttttaag atcattatgt gcaaaacacc 2520 aagttttaaa aataactcac agaatggcct tagttttcaa tgtctgatgg tatatttgtg 2580 agttgtgtta tctgtaatat acatcccaga ataaaggagt gaattaaata gtttaaaaaa 2640 aaaaaaaaaa aaaaaagatc tttaattaag cggtc 2675 51 168 DNA Homo sapien 51 acaacacaac ctgttaggta gcaggctggg tattacctga gtaaaaagtc cctattcttt 60 ccatttctcc atgctattta aaagcatgtg gtgatccttc aataaattaa agatataaca 120 aattatttga tgccattagg cggcctggat caccaattct aagtcttt 168 52 1139 DNA Homo sapien misc_feature (291)..(576) a, c, g or t 52 caaaattgga ttcttcaaaa cgccaggttg gcctttcttg actccaaaag aggtgactct 60 tgtagcattc ttacaggcct aacatagcac ttactttatg ttgcaatgct gtgtgcaatg 120 ctgtgttttt ttactcacta gctctgagca aaacattatt tattcttggt aattgtaaca 180 cttggtagtg aagacatatt ttttggccat ataatggatt atactttgta tttgaatcca 240 tgtgaatcag tagcatattg gtcttcattg tttttcctcc ttctccgacg nnnnnnnnnn 300 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 360 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 420 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 480 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 540 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnntaac catatttttt ccaattatta 600 aaaaatcttt tttcccccta aggaatgtgt ttctaaggtc accatgtttt tagtgcttca 660 gtttgacttg tctacatcta aagttaactc tttaaggctt acatttatga ttataattct 720 ttccatcgag ggatttagtc tccattattg tcatgtttct tgattttttt cattatactt 780 agttcttctt ttgtctaggt tttatatata ccttaattaa ttctttcttg gctgttttat 840 atctatgttg ctgtcagcat gggaatctct attattagaa agctattaac ttttaaaata 900 tgtatctttg gtgatttctt tgtcctaaca gtttagatgg cctgttgctc ttctaaatct 960 taaatcatag gtattctatt ttggttgttg tgtttcatta cactgtcata gtttttgata 1020 ttttcattac tattgaggta ctgtggttta ccaatgttct gttggtacga atactttcca 1080 tctgttgggg agctcaaact gggaaccagc acgttcgtga tgttcgcacc ccccacccc 1139 53 681 DNA Homo sapien 53 ggtacgggga gaacatatca aaaaggggaa ggatggattc ccttgatgcc caggattaca 60 gtggcaccta aagcacattt ttttttttct gagccaacca gctaaaggat cactgcagct 120 aaatacagat agagaagcaa caaagccagg caaataccca tcagagacag tgacaagagc 180 agctgggggc acgggggagg cggaaggaag agaaagaagg ggaggagcct ccagagtccc 240 agccccaacc ccctctgcca tgggctaccc ttgctcccca aaaatcccgt tggggttgaa 300 gtgaggagga ctgcaggctg gggtgaaaat acacaaggac agcccaacaa aatacaacaa 360 ggactagcat cagtctcccc cttactccga cccccaagaa aaataccctt attggtgact 420 agtatttatg aaaatctgta aggagactat tctatgtagt gggctctaat cccatataca 480 cagcagctgc ctgtgtgggg aaccttttca aatcagtgat tgcgggaaca aacagtattt 540 tcagcttctt acggtgccca tgcaggcttt taccaagacc ttggttaagt cccagtcaca 600 tttactttct gtcttcatct agaaaagggt gaggaaagag ggagggacaa ggtgctccag 660 gtgctagtaa gctgggtatc c 681 54 3191 DNA Homo sapien 54 gtgctgccga gtagtcccgg aagcgaagca gcgatggcgg agagtccgac tgaggaggcg 60 gcaacggcgg gcgccggggc ggcgggcccc ggggcgagca gcgttgctgg tgttgttggc 120 gttagcggca gcggcggcgg gttcgggccg cctttcctgc cggatgtgtg ggcggcggcg 180 gcggcagcgg gctcccgccc tcagccgctg cccacggggc cgcgctgctt agccactggg 240 accccacgct cagctccgac tgggacggcg agcgcaccgc gccgcagtgt ctactccgga 300 tcaagcggga tatcatgtcc atttataagg agcctcctcc aggaatgttc gttgtacctg 360 atactgttga catgactaag attcatgcat tgatcacagg cccatttgac actccttatg 420 aagggggttt cttcctgttc gtgtttcggt gtccgcccga ctatcccatc cacccacctc 480 gggtcaaact gatgacaacg ggcaataaca cagtgaggtt taaccccaac ttctaccgca 540 atgggaaagt ctgcttgagt attctaggta catggactgg acctgcctgg agcccagccc 600 agagcatctc ctcagtgctc atctctatcc agtccctgat gactgagaac ccctatcaca 660 atgagcccgg ctttgaacag gagagacatc caggagacag caaaaactat aatgaatgta 720 tccggcacga gaccatcaga gttgcagtct gtgacatgat ggaaggaaag tgtccctgtc 780 ctgaacccct acgaggggtg atggagaagt cctttctgga gtattacgac ttctacgagg 840 tggcctgcaa agatcgcctg caccttcaag gccaaactat gcaggaccct tttggagaga 900 agcggggcca ctttgactac cagtccctct tgatgcgcct gggactgata cgtcagaaag 960 tgctggagag gctccataat gagaatgcag aaatggactc tgatagcagt tcatctggga 1020 cagagacaga ccttcatggg agcctgaggg tttagaccct gctcccatct ccccttcccc 1080 cactcaagag tcccagcaga atcccttccc cccaccccag ggatggagag gcactgtgta 1140 tctccctcca gactcgaagt catcctgcaa gatggcaaga accaagcaag ctccgatccc 1200 agggtgtggg agtgggggcc tgttcccggt ctgacctcct tggcactgga gcatctgggg 1260 cttcgttcat ccattcatcc cgtatcaggg ggccaaggta cctttacagg agcacctaga 1320 gcgagggcct ttggcaaaaa caaaacaacc aacacacctc tccacagggc cagctcctta 1380 gggataagtg gaagatggaa attgcaattc caagagggag tgtgcccaaa tgatttatgg 1440 ggatacctgg aagggagctt ggggtggggg ctgtctgtga cacttaagca gtctgggtgg 1500 ttgtctattt gtctgtcttc agtcttgaag cagggcttcc caatgccctt ttcctccctg 1560 ccttccttcc cccattattt cccacaggcc agcataattt tgtttttcct aatttatagt 1620 cactgttcta gacagaccaa agagaaggaa cagtggtgga gtctaggctg ctgatcagta 1680 agctttacct agcacctgag cacctttctc ccctcccctc tttcctcacc cttttctaga 1740 tgtaagacag aaagtaaatg tgactgggac ttaaccaagg tcttggtaaa gcctgcatgg 1800 caccgtaaga agctgaaaat actgtttgtt cccgcaatca ctgatttgaa aagttcccaa 1860 cacaggcagc tgctgtgtat atgggattag agccactaca tagaatagtc tcttacagat 1920 tttcataaat actagtcaca ataagggtat ttttcttggg ggtggagtaa gggggagact 1980 gatgctagtc cttgttgtat tttgttgggc tgtccttgtg tattttcacc ccagcctgta 2040 gtcctcctca cttcaacccc agggatttgt ggggagcaag ggtagccaat ggcagagggg 2100 gttggggctg ggactctgga ggctcctccc cttctttctc ttccttctgc ctcccccgtg 2160 cccccagctg ctcttgtcac tgtctctgat gggtatttgc ctggctttgt tgcttctcta 2220 tctgtattta gctgcagtga tcctttagct ggttggctca gaaaaaaaaa aatgtgcttt 2280 aggtgccctg taatcctggg catcaaggga atccatcctt cccctttttg atatgttctc 2340 cccgtacttc cagatttatt gttatggctc ccagtgggta ttggcgattc ttgtgatgca 2400 gggcctcagt cagtgtccag ccatgcataa gggagaggat agtgtgtacc tgccctgccc 2460 tctgctatga aggtctctgc cttgtggatc atgggactcc ccttggagga tctgtgcaaa 2520 ggggggctgg gcacaaagga gaatgtccta tttgggaggg caggaagcaa aggaactgga 2580 cagggattgg tgggcttggg gaacggaagt ttatcttgga tacccttgaa gaggctgggt 2640 ctcttcacat gaagatcgaa aagggaccct gcttccaatt tccctcttcc attcctcgag 2700 ctactccagg gctcagaaga atgctcttgg tctgtgggtc cagtgttgtc tgtcatccat 2760 ttaagtgttc ccactttcaa gtgacaatcc tctccttggc cctgccatag ggcagagcat 2820 gtctggcata gcagcctgac ttttatgccc taatcttgag ttgaggaaat atatgcacag 2880 gagtcaaaga gatgtcttta tatctgactg ttataaatga agttttgcgt tctgttgggt 2940 tcccttttgg ctgccatcaa cgtcgtcttg cacgccagac gtgctgggga ttggagggct 3000 tggttcagca cgcattggtc ctttgtcacc ccctcctagg ccgttgtggg gcacgacgcc 3060 cgattgttgg accccttctc tgtcgcggcg gcgtggcgca cgccttctcg agggccacgc 3120 cccgccttgg gcccgcccct ggggctcagg aggcctcctg gtgcgcgtct ccgggcgcct 3180 cccgcaccgg t 3191 55 385 DNA Homo sapien 55 actgctaacc cctgccaggc ccagctgcca caccctttct gggagaagca tggcctacag 60 aatgaagagg gggaccagga acccctgtgg gagaggctta gacctgaagc agtgcccact 120 ctggctcctc ctgccttggc tgactgggtt cctggaccat gtgcatttca ctgggccatg 180 ggatctacat ctccttgcat ccccagctgg tctgatccct gccagggccc cttccttcct 240 gctcatggtc ttcaggtggc ctgatcatgg aaagtaagga gttaggcatt accttctggg 300 agtgaaccct gactccatcc ccctattgcc accctaacca atcatgcaaa cttctccctc 360 cctggggtaa ttcaacagtt aaaag 385 56 1977 DNA Homo sapien 56 ttcacccggc cctcgcctgt caccttcaca gagaaggggc tgcctgcagg aagaaagcac 60 ggcccacgcc cctccagtca catactgcct gtgggccctg gtgtagtgag gggggctgcc 120 gaggcactgc tgcactcacc aggcacgtgc tggtcggcaa acttgatgtt gatgatgtag 180 ttgcctggct ctgtggggca gtaggtcacc tggcgggaca ggtgcctggc tgctacaaac 240 catgcaatga gccatgcccc gccctggaca cccccgccca gcatctgggc ctccacgctt 300 gggaccgtgg gagcggccaa cagagctatg tctggagaca tatgataaac cacctcagcc 360 cccaccaagc cgccgcaccc gtagaccaga ccccaaggac cctggccacc atgggccaga 420 gagcattacc ttcatctctg gctctgctga gccggccctt gagtccccca cctgctgcct 480 gctctggcga ccctgggtgt gggagtggtg ccgggctgcc ttctgcttcc gcccgctgcc 540 gggattgcct ccagcgctgt ggaggcctgt gtgcggggat gcagcccctg cctgtctact 600 gaggactccc actgagggga ctgctgaagc caactggtgc caaggagcac aatggagtgc 660 cccccagccc tgatcgtgca ccccccagac cggcgggatg gccaggcggg ctgcaagtca 720 accatgggca gcagcttcag ctaccccgat gttaagctca aaggcatccc tgtgtatccc 780 tacccgagag gccacctccc cagcccctga tgcggactcc tgctgcaagg agccactggc 840 cgatccccca cccatgcgag cacagcctgc ccagcacctt tgccagtagt cctcgtggct 900 ccgaggagta ctattctttc catgagtcgg acctggacct gccggagatg ggcagtggct 960 ccatgtcgag ccgagaaatt gatgtgctca tcttcaagaa gctgacagag gctgttcagc 1020 gtacaccaga tcgatgagct ggccaagtgc acatcagaca ctgtgttcct ggagaagacc 1080 agtaagatct cggaccttat cagcagcatc acgcaggact accacctgga tgagcaggat 1140 gctgagggcc gcctggtacg cggcatcatt cgcattagta cccgaaagag ccgtgctcgc 1200 ccacagacct cggagggtcg ttcaactcgg gctgctgccc caaccgctgc tgcccctgac 1260 agtggccatg agaccatggt gggctcaggt ctcagccagg atgagctgac agtgcagatc 1320 tcccaggaga cgactgcaga tgccatcgcc cggaagctga ggccttatgg agctccaggg 1380 tacccagcaa gccatgactc atccttccag ggcaccgaca cagactcgtc gggggcaccc 1440 ttgctccagg tgtactgcta acccctgcca ggcccagctg ccacaccctt tctgggagaa 1500 gcatggccta cagaatgaag agggggacca ggaacccctg tgggagaggc ttagacctga 1560 agcagtgccc actctggctc ctcctgcctt ggctgactgg gttcctggac catgtgcatt 1620 tcactgggcc atgggatcta catctccttg catccccagc tggtctgatc cctgccaggg 1680 ccccttcctt cctgctcatg gtcttcaggt ggcctgatca tggaaagtaa ggagttaggc 1740 attaccttct gggagtgaac cctgactcca tccccctatt gccaccctaa ccaatcatgc 1800 aaacttctcc ctccctgggg taattcaaca gttaaaagaa gcttatctta aatgtattgt 1860 attggggggt gggcagggcc cactctatgt tatgttaagg agttggttct ggttcttggc 1920 tgatgttctg tatcttaaca tgaccacagt ttgtaagtac ctcgctcgcg accacgc 1977 57 629 DNA Homo sapien 57 tgggtgatct agtctgtcga gcgcgcatgt gatggatagc gtggtcgcgg gcccggaggt 60 tacatggtgg cctatacaaa agcactccat gtttctgcct gaataacgta cgttgatcgc 120 ttggttgcct gagcaaatgt ataagggagc tgcttggagg ggaaaggaac acaataaaac 180 gcctctggag gtatttcaaa gagtagtttc tcaaatctct ctgattcagg aagaggatga 240 cgagagggag agaacgtgga attacttaaa gtcatctaac tcattggtct tgttcaacaa 300 gaaagaattc tggtttgtgg ctgaatctga tttaacagct gccaatagct cattacttct 360 aagatgtata tctaattcaa aactagatgc tcccccctcc ctcttttttc cctaaaagct 420 gggaacttgt aagtaaatgg cctagtgaaa tagacactgg ctattttaga aaaagggtca 480 gaaggtagac caggaactat gtatcaagaa gaagtaagtg aggctcaagc ccaggccacc 540 taggctgtgt ttattcagtc cacccaatcc aatgtcaaag ccccaagtgg gccagtgtta 600 cctttatctt cccatctttg tatttctga 629 58 3535 DNA Homo sapien 58 gtgataggca gctttccttc ttttcaacag tgatacctac gaaaatcaaa ataaatgcaa 60 gctgaggttt tgtgctcact gaaagggctg tcaaccccag aaggccgaca caaaaaaaat 120 ggtatgtgaa gatgcaccgt cttttcaaat ggcctgggag agtcaaatgg cctgggagag 180 ggggcctgcc cttctctgct gtgtcctttc ggcttcccag ttgagctccc aagaccagga 240 cccactgggg catataaaat ctctgctgta tcctttcggc ttcccagttg agctcccaag 300 accaggaccc actggggcat ataaaaaagt caaaaatcaa aatcaaacaa caagttctga 360 gttacttagg aaacagactt cgcatttcaa tcagagaggc cacagagcaa ggtctaaact 420 tctggcttct agacaaattc ctgatagaac atttaaatgt gggaagtggc ttccccaggt 480 cccatcccct gtttagggat agagttgata tcatttttat aggtgccatg tatgcctctg 540 cctgaatttt tttaattgac ttttgagctt ttgagattgc acgagggaga acaaggcctt 600 tgctgttgtg gataggaaag acttaaccta aaattaaacc agcaagaaag cattagtaaa 660 aatctaacaa tatgaagggc tcttatgagt catttttttc aaaagatgaa aactccagaa 720 acgcacagga acgaaatacc tcccagaaac atgaagcaat catcgaagac tcactggtaa 780 tatttttaaa aagtatacag atcaaagcaa aaagaagcca tgtgtaacaa agagaaatgt 840 gcaaatattt tttaaggcag tattaagtgc aagaggagta acatgaaata aacattcttt 900 cacatggcta ctgggaatat aaatttcgct ccagaaaggc cgtagcagtt tgacgatagg 960 tggcaaaacc ttaagattgt gtactggggc ccagaatttt tatttctagg aatgtatcct 1020 gaggaaatta tccgagatcc ccacaaactg caatgtttag gaattgtcct tatagcattg 1080 catacacaag aaaaacagag aaaagcctga tccctgtcag tggaaaaggg gttcaatgaa 1140 ttacggtgtg tctgcatgag gcttttatga cattaaaaat tgttgaacaa cggcctggca 1200 cagtggctca tgcctgtaat cccagaactt tgggaggcca aggtgggcgg ataacttgag 1260 gtcaggagtt tgagactagc ctggccaata tggtgaaacc ccgtctctac taaaaataca 1320 aaaattagct gggcgtggtg gcaggcgcct gtagtcccag ctgctcggga ggctgaggca 1380 ggagaatcgc ttgaacccgg gaggcggagg ttccagtaag ccaagatcgt gccactgcac 1440 tccagcctgg gtgacaagag tgagactccg tctcaaaata aaaaaaaaaa aaaaaagtaa 1500 aacaaaaata aagtctatgc ccattaagac gtcttctaat tcagttgtga ttgtctgctc 1560 ctacttaaaa aaatatttaa gcttgatgtt taattattcc ctttcagcaa atttggatca 1620 gaaaattaaa gtatgtgaca agatcaggtc accttgaatt tccacacaat ctcaagacac 1680 tgaatagcaa aaaagtaaca ttacacagta atgattagga tatttcctta gactttgctg 1740 gatctttggt cttaaggtaa catgtaaaag tagtgaagcc tttcctttca tggccctgtg 1800 caatgtaacg gttttctgcc tcctcttcag ctggaagcgt tagtggtagt atgggcacag 1860 aatatatgta cactggcgat gctgaccatg cctcccaggt accctggctc tgggttcctt 1920 gacctaggga acaagattgg atgaggcaga tctttgagcc catgtgacta tagaatttgc 1980 tgatgatata attttacaat aacaatggat aggaatttta cctctctttt tattagttta 2040 atattattta atattatgta cataagtgtt cactcgccta attaaaaaca ttgagtaaac 2100 caagttttta tatagactac ccttgccata tgatgctctt tttctctaat aatatgcagt 2160 ttaaatcctg aggaatcaat gcccagcatt tcaccacatc tgaactctgt gtgggcattc 2220 ttcactcgcc tacaaggggt aaacaaggct accagaactt gaatttgact tatagggagc 2280 tacccaggaa ggggaaagcc cttgggactt tttccaaaac aatcttctat ttgaactgtt 2340 catcagccaa agtagtccac tgaggtgaca aagctttcag aaatacaaag atgggaagat 2400 aaaggtaaca ctggcccact tggggctttg acattggatt gggtggactg aataaacaca 2460 gcctaggtgg cctgggcttg agcctcactt acttctcctt gatacatagt tcctggtcta 2520 ccttctgacc ctttttctaa aatagccagt gtctatttca ctaggccatt tacttacaag 2580 ttcccagctt ttagggaaaa aagagggagg ggggagcatc tagttttgaa ttagatatac 2640 atcttagaag taatgagcta ttggcagctg ttaaatcaga ttcagccaca aaccagaatt 2700 ctttcttgtt gaacaagacc aatgagttag atgactttaa taattccact tttctctccc 2760 tctcttctcc tcttcctgaa atcagagaga tgagaaacta ctctttgaaa tacctccaga 2820 ggcgttttat tgtgttcctt tcccctccaa gcagctccct ttatacaatt ttgctcaggc 2880 aaccaaggac agagtatcgg cagaaacatg gagtgctttt gtataggcca cctgtacata 2940 aaagtgtaat tatttattta attttcccat ttgtatcata ttaaagcttt gtacagtgtt 3000 ttaagttctg ttttaaaatt attttgtatt ttatttttat aacctagtaa taaaatattc 3060 attccgcatg caaaaaaaaa cacacacaca acccaaacaa ccaaaaacaa acagaaccaa 3120 aagatagaaa ccaaacacag caacagacag acacaagaga agacgaaaac aaccacacaa 3180 acagcacaca caaccgcagc ggagaaccaa caaagccaaa cgcaagacag cacaacaagg 3240 gacaaaacac acacgtagca caaagcagcc gcagaaccga acacacatct aaagacaggc 3300 gacaacaaca tagcaggccg tagcaccgac aaccactaaa ccataactat ccagcggaga 3360 tcagatcaca gaagccgaca cagaaagaaa agcatgtatg caacgcatga caccgcaggg 3420 cggataaaaa cactcgtagg cgggaccgcc gcagaacgat cgaaggctaa caaacaagct 3480 agtagatcac aagtacgtga ccacgccctc ttatctataa aggaggaaga gggag 3535 59 348 DNA Homo sapien 59 cgaatgatgc tatatagggc catgggtgca ctgatgcatg gctcgagcgg ccgcagtgtg 60 atggatcgcg gcgaggtact tctgccatca ttttattcca ttccagcgct ctggcatgca 120 agataatcca tctctaaaat tcaagacttc caaattgaga tgaacgatta tgggcttggg 180 ttggggttta taaccaatcc gatcattgat catttgttcc cggctcttgg gatcactgct 240 aagcccaatg gctccttctc catcactgcc tcctacaact tccacatctt ccttctgttt 300 cttacgggtc tccaggtcct ttcgaatgtt ctcaaactct tcaatgtc 348 60 2497 DNA Homo sapien 60 ttatacccta tgctcgacca cttggagtgt tcaacctcgt tcaccggggt tttaatggtg 60 aaaccacgct tgctcgtccg tgtttcttgg aacgcttgcc ctgtaccata cctatgcgcc 120 cgtggtctat acggaagggt ctaaaacttt tctacggcta atgcggccca caaagttttt 180 tctttgtgtg tttttgtttg gatgcctcac agtggtccaa aatatattta tttttaaaaa 240 cagaaaatca gatcagtttt atagagtcaa attttcaaga gacaaaccag agtttggatt 300 ccagcttaga gtgcaagtga agcatcagta atctcatgca gaagatttgt ctctgcagga 360 ggtacattct gcttgactgc aagcactcaa ttctctaaat ctggtttgta cttctgccat 420 cattttattc cattccagcg ctctggcatg caagataatc catctctaaa attcaagact 480 tccaaattga gatgaacgat tattgggctt gggttggggt ttataaccaa tccgatcatt 540 gatcatttgt tcccggctct tgggatcact gctaagccca atggctcctt ctccatcact 600 gcctcctaca acttccacat cttccttctg tttcttacgg gtctccaggt cctttcgaat 660 gttctcaaac tcttcaatgt catcaagctt tagctctagg cgtgttggtt tccgtctcag 720 catactgaag tcaacactaa gggccaaacc cagtgaacta ttagcaattc acaggattat 780 cctccgcgtc caaacagatc ttaaatgtgt acgtcattca ttaaacaaac acttcttgtg 840 ttccagctac agagttaaaa ggtacagtca taatctcttt tcaagccggc ctagcccctt 900 cccggaacct cggctccccc ccaacgaaac tactgctaag ccaactggac tacacttccc 960 agactgcttg gagcctctct ctccgcagaa cctcgtcttc cgcgagcttt tcctggaggt 1020 tctaggaggg atgcccctca atgccacgac gccatttcct actacgactt ccatcatgct 1080 ccgcgccgct ccgggggcgg tgacccctct tggcccacgt cttgtcagtg acgcacttcc 1140 tgcaaccaaa actaaagcac ccgacgactt agttgctccg gtcgtgaaga aaccacacat 1200 ctattatgga agtttggaag agaaggagag ggagcgtctg gccaaaggag agtctgggat 1260 tttggggaaa gacggactta aagcagggat cgaagctgga aatattaata taacctctgg 1320 agaagtgttt gaaattgaag agcatatcag cgagcgacag gcagaagtat tggctgagtt 1380 tgagagaagg aagcgagccc ggcagatcaa tgtttccaca gatgactcag aggtcaaagc 1440 ttgccttaga gccttggggg aacccatcac actttttgga gagggtcctg ctgaaagaag 1500 agaaaggtta agaaatatcc tctcagttgt cggtactgat gccttgaaaa agaccaaaaa 1560 ggatgatgag aagtctaaaa agtccaaaga agagtatcag caaacctggt atcatgaagg 1620 accaaatagc ttgaaggtgg caagactatg gattgctaat tattcgttgc ccagggcaat 1680 gaaacgcttg gaagaggccc gactccataa ggagattcct gagacaacaa ggacctccca 1740 gatgcaagag ctgcacaagt ctctccggtc tttgaataat ttttgcagtc agattgggga 1800 tgatcggcct atctcctact gtcactttag tcccaattcc aagatgctgg ccacagcttg 1860 ttgtgatgaa ccagtggcag atattgaagg ccatacagtg cgtgtggcgc gggtaatgtg 1920 gcatccttca ggacgtttcc tgggcaccac ctgctatgac cgttcatggc gcttatggga 1980 tttggaggct caagaggaga tcctgcatca ggaaggccat agcatgggtg tgtatgacat 2040 tgccttccat caagatggct ctttggctgg cactggggga ctggatgcat ttggtcgagt 2100 ttgggaccta cgcacaggac gttgtatcat gttcttagaa ggccacctga aagaaatcta 2160 tggaataaat ttctccccca atggctatca cattgcaacc ggcagtggtg acaacacctg 2220 caaagtgtgg gacctccgac agcggcgttg cgtctacacc atccctgctc atcagaactt 2280 agtgactggt gtcaagtttg agcctatcca tgggaacttc ttgcttactg gtgcctatga 2340 taacacagcc aagatctgga cgcacccagg ctggtccccg ctgaagactc tggctggcca 2400 cgaaggcaaa gtgatgggcc tagatatttc ttccgatggg cagctcatag ccacttgctc 2460 atatgacagg accttcaagc tgtggatggc tgaatag 2497 61 604 DNA Homo sapien 61 catctgatca cgtcgcccgc cctagtctgc ttttgtgaat ctccactttg ttcaaccccc 60 acccgccgtc tctccctccc tgcgccttcc ctctaacctt aaagacccag ctacctctac 120 gcaaatggta gctacctctg cgcaggtgga agttgagttc ggttcacgcg ggaccctctt 180 ccctgtggca agctgctgaa ggagacctgc tgttactgct ttagctgctg ttctgcttaa 240 tctcagacag ctggaaggta gtattccgcc ctcgcccagc cacccgagta aatgagaatg 300 atgactgact gagaccctga tggtggtggc ttaggcttaa tctcagacag ctggaaggta 360 gtattccgcc ctcacccagc cacccgagta aatgagaatg atgactgact gagaccctga 420 tggtggtggc ttaggcaaga tgaacgtctg aaatggaggc ccagggctgc cacgatggct 480 ctgtagtcat cagggaggga gctcctttta tcttgttacc tactcccctc ttgtgcccct 540 ttcttccctt gatctaagaa ggttgctccg ggatctcgcc atctggcctg cgttcaatca 600 gcag 604 62 4733 DNA Homo sapien 62 atggagagaa accagaacag aaaagtggaa aattccaaaa accagagcgt ctcttctcct 60 ccaaaggatc acagctcctc accagcaagg gaacaaaact ggatggagaa tgagtttgat 120 gaattgacag aagtaggctt cagaaggtca gtaataacaa actcctccga gctaaaggag 180 catgctctaa cccatcacaa ggaagctaaa aaccttgaaa aaagtgttaa cactcctgtg 240 gacgttttgt ctttgttttt caccccagtc cacacctctg ctgttagtga ggggctcctg 300 gtcatcacag ccacatgtgg actcccctgc tctgtacctc ccagcctttc tgccaacagc 360 actggcctca cagtgctgtc ctggggattg agtgagatag ctataatgtg gagtcgctgc 420 tgcctgctaa ctcgcccaga cgttcttcga gtgtcacatt tgaagacgag cactgaggat 480 gaggaaccaa ctgaagaata tgaaaatgtt ggaaatgcag catctaagtg gccaaaagtg 540 gaggatccta tccctgaatc taaggttggt gacacatgtg tttgggatag caaggtagag 600 aatcaacaga aaaagcctgt ggaaaacagg atgaaggagg acaaaagcag catcagggaa 660 gcaatcagca aagccaagag tacagcaaat ataaagacag aacaggaagg tgaggcatct 720 gagaagagct tgcatctgag cccacagcat atcacacacc agactatgcc tataggacag 780 agaggcagtg agcaaggcaa acgtgtggag aacattaatg gaacctccta ccctagtcta 840 cagcagaaaa ccaatgctgt taagaaatta cataaatgtg atgaatgtgg gaaatccttc 900 aaatataatt cccgccttgt tcaacataaa attatgcaca ctggggaaaa gcgctatgaa 960 tgtgatgact gtggagggac tttccggagc agctcgagcc ttcgggtcca caaacggatc 1020 cacactgggg agaagccgta caagtgtgag gaatgtggga aagcctacat gtcctactcc 1080 agccttataa accacaaaag cacccattct ggggagaaga actgtaaatg tgatgaatgt 1140 ggaaaatcct tcaattatag ctctgttctg gaccagcata aaaggatcca cactggggag 1200 aagccctatg aatgtggtga gtgtgggaag gccttcagga acagctctgg gctcagagtc 1260 cacaaaagga tccacacggg ggagaagccc tatgaatgcg acatctgtgg gaaaaccttc 1320 agtaacagct ctggccttag ggtccataaa aggatccaca caggtgagaa accttacgaa 1380 tgtgatgagt gtgggaaggc cttcattact tgtagaacac ttctcaacca taaaagcatc 1440 cactttggag ataaacccta taaatgtgat gagtgtgaga aatcttttaa ttatagctct 1500 cttctcattc agcataaagt catccacact ggagagaaac cttatgaatg tgatgaatgt 1560 gggaaggctt tcaggaacag ctcaggcctc atagtgcata aaaggatcca cacaggagag 1620 aaaccttaca agtgtgatgt ctgtggcaaa gcattcagct atagctcagg cctcgcagtc 1680 cataaaagca ttcaccctgg gaagaaagcc catgaatgta aggagtgtgg gaaatccttt 1740 agttataact cactacttct tcaacacaga actattcata ccggagagag accttatgta 1800 tgtgatgtgt gtgggaaaac gttcagaaac aatgcaggcc tcaaagtcca caggaggctc 1860 catactgggg aaaaaccata taagtgtgat gtgtgtggga aagcctatat ctcacgctct 1920 agccttaaaa atcacaaagg aatccacctt ggggagaagc cctataaatg tagctattgt 1980 gagaaatcct tcaactacag ctctgccctt gaacagcata aaaggattca taccagggaa 2040 aaaccctttg ggtgtgatga gtgtggtaaa gctttcagaa ataattctgg ccttaaagta 2100 cataaacgaa tccacactgg ggaacgacct tacaaatgtg aagaatgtgg gaaagcatac 2160 atctctctct cgagccttat aaatcataaa agtgtacacc ctggggagaa gccctttaag 2220 tgtgacgagt gtgagaaggc cttcatcaca taccgaaccc ttacaaacca caaaaaagtt 2280 catcttgggg agaagcccta caaatgtgat gtgtgtgaga aatcttttaa ttacacatcg 2340 ctcctttctc agcacagaag ggtccacact agagagaaac cctatgaatg tgacaggtgt 2400 gagaaggtct tcagaaacaa ctcaagcctt aaagttcata aaagaatcca tactggggag 2460 aggccctatg aatgtgatgt gtgtggaaaa gcctacatct cacactcaag ccttattaac 2520 cataagagta cccaccctgg caagacaccc catacatgtg atgaatgtgg aaaagctttt 2580 ttctcaagca gaactcttat aagccataaa agagtccatc ttggggagaa acccttcaag 2640 tgtgttgagt gtgggaaatc tttcagttac agctctctcc tttctcagca caagaggatc 2700 cacacagggg agaaacccta tgtgtgtgat aggtgtggga aggccttcag gaacagctca 2760 ggcctcacag tgcataaaag gatccacaca ggtgagaaac cctatgaatg tgatgagtgt 2820 gggaaggcat acatctcaca ctcaagtctt atcaatcata aaagtgtcca ccaggggaag 2880 cagccctata attgtgagtg tgggaaatcc ttcaattata gatcagtcct tgaccagcac 2940 aaaaggatcc acactggaaa gaagccatac cgatgtaatg agtgtgcaca tatacccaac 3000 gccaccgcgg acctcatgaa agtggaccat gaagaggagc cccagctctc cgagccctac 3060 ctttctaaac aaaagaagct catggccaag atcttggagc atgatgatgt gagctacctg 3120 aagaagatcc tcggggaact ggccatggtg ctggaccaga ttgaggcgga gctggagaag 3180 aggaagctgg agaacgaggc actttcccag tggaaagaat ttgatgccat ttccgcacac 3240 ccaaattcct gttggcagga taatcagcaa gtaatacaga gagctgcttc cttcaacagc 3300 tgcattcagc acaaaaccga gggccgatta tgtggagaaa tatccttcag agaagcatgt 3360 gatctttgtt ctgccttttg ccctttgaag catatgatct ttgttcctac tccctgttcg 3420 tacactccct ccccttttga aatccttaat aaaaacctgc tggttttacg gctcaggaag 3480 cttctgctga ttgaacgcag gccagatggc gagatccgga gcaaccttct tagatcaagg 3540 gaagaaaggg gcacaagagg ggagtaggta acaagataaa aggagctccc tccctgatga 3600 ctacagagcc atcgtggcag ccctgggcct ccatttcaga cgttcatctt gcctaagcca 3660 ccaccatcag ggtctcagtc agtcatcatt ctcatttact cgggtggctg ggtgagggcg 3720 gaatactacc ttccagctgt ctgagattaa gcctaagcca ccaccatcag ggtctcagtc 3780 agtcatcatt ctcatttact cgggtggctg ggcgagggcg gaatactacc ttccagctgt 3840 ctgagattaa gcagaacagc agctaaagca gtaacagcag gtctccttca gcagcttgcc 3900 acagggaaga gggtcccgcg tgaaccgaac tcaacttcca cctgcgcaga ggtagctacc 3960 atttgcgtag aggtagctgg gtctttaagg ttagagggaa ggcgcaggga gggagagacg 4020 gcgggtgggg gttgaacaaa gtggagattc acaaaagcag actagggcgg gcgacgtgat 4080 cagatgacct gtgcgggcgg cagcctcctg ccctcctccc cttcgtgcgc cggctggagc 4140 gaagagttct tttgacagcc gtgagcttcc ccgccaggaa cttactgggg ctgcatcacc 4200 ctagaaacgt ggctttgggc tgtggaaacg ctgcctctgt ggaagtctct cctcgcgggg 4260 gtggacgggt cgctgcgcgc ccagcgttct tctgcggttc tcacagcccg cccgccgccg 4320 ccgcctcggg gaccctttgc ggggaggcct caggtcagcg ccgccccttg cgatggcggg 4380 agagcagagc ggccccaggg cctctgagct ccggccccgg cacgtcccgc cctctcctcc 4440 gcttgcggga gccggggcgc ctcggaggga aaccttcccg gacacaggcc gggagaagag 4500 gggcccgtgg cgccatcggc gcagcgttcc tggtttcggc catgtttttt tttttttttt 4560 tgagacggag tttcgctctt tttgcccagg ctggagggca atggcgccgt ctcggctccc 4620 tgcagccgcc gcctcccggg ttgaagggac tctccggcct caggccgcgg tgttcttgta 4680 aattagaacc ggcctatgcg ccaagcgcgg gtctcgcggc tgcggagaga ggc 4733 63 577 DNA Homo sapien 63 aaaaacaaac aaaaaaacca gttatttact tggctataac aatgtctgta aatggtaaag 60 acagaaaaca acctaagttg ttcattgggg gactagataa atttaaattg gttacattcc 120 atacaatgtg gaagataaag tagctgtgag gaacgatgcg cctcctccct ttacagatgt 180 ggaatgaccg ccaagataca gccaggaaaa aagcaagaag agaacagttg gtgatctgct 240 gtttcagttc aaaataacca attttaaaaa aatgtctcta gaaggctaca taagaggctg 300 gtgagacagt ggtcctgtgg gagggaatgt gggtaacagg caacaggatg ggagggatgg 360 tcaccataca tcttttggca cactctgcat tttgaaacat atgattggtt ttccctagtc 420 taacaaaata actttaggtc caactgactg tagtaaattg gtcactagca aaaaaaaaaa 480 aaaaaacaaa aaaagcgtgg ggggaacccg gggccaacgc gggtccccgg tggggaatgg 540 gtttcccggc tccaatttcc ccccattttg cgcacaa 577 64 744 DNA Homo sapien 64 aaaaacaaac aaaaaaacca gttatttact tggctataac aatgtctgta aatggtaaag 60 acagaaaaca acctaagttg ttcattgggg gactagataa atttaaattg gttacattcc 120 atacaatgtg gaagataaag tagctgtgag gaacgatgcg cctcctccct tacagatgtg 180 gaatgaccgc caagatacac agccaggaaa aaagcaagaa gagaacagtt tgtgatctgc 240 tgtttcagtt caaaataaca atttaaaaaa atgtctctag aaggctacat aagaggctgg 300 tgagacagtt gctctgtggg agggaaagtg ggtaacaggg aacaggatgg gagggattgt 360 caccatacat ctttttgcac actctgcatt ttgaaacata tgattgtatt tcctagtcta 420 acaaaataac attaggtcca actgactgta gtaaattgtc actagaatct ttgtcttgga 480 gtcatttgat tttatttttc acagaagggc atatggttag atagcctaaa acagcagggg 540 agggagcagt gtgtgctagg agctgccaca tgccaggcac ctgatagata ccagctctat 600 ctcacgctcc ccctgtccct tgaggtaggt gtttctgttt ctacttacaa gaaaatagac 660 taaggcgtaa agtaacacaa tcacggtcac acatgtggca agcagcacag cctggatttg 720 aagctaggca agtctgactc taag 744 65 318 DNA Homo sapien 65 taagtgtttt aaagaaacta gagcagcaga gaagagagac tcagaagccc gtggcacggc 60 tttctcggcg tcccctccag cgagggggtc tccattgctg cagttgccgg ttttgtccaa 120 ccaggtcagg aggctgcccg gccccctccc cactctcaaa gttgcttgtt aaacacagag 180 tcgtaatttg tggctaaata taactagtgt gttctcacgg aaagtataat tcagggtgct 240 cattgtatga ggttatcaac aagacccatc tgggttaaat taaagtgatt ttcataaagg 300 gcagaagcgc ccctttac 318 66 2505 DNA Homo sapien 66 ctgcgccccc aataatcgtg tgttgggtat ctctccattg ttccctgggc cattagtcaa 60 agggcaaatt agaaacaatt tcttgacgac aaaaattgac tcttaattct tcccaccaga 120 ggcgcagggg gacaagtcca gaggccaggc ctgaggctgg ggctggcggc aggaggggta 180 ggcggggtag aggtggggta gaggtggggg atctaagatg gttcacagca cagagacctc 240 cctcaactgg agggcagcag cagctcaccc ccaccccaga atcagtgttc cagaggacag 300 ctgggggcag ggggttagga acaatcccac tccctcctgg aagaggtcct gaccccccac 360 cccacccatc tgcctgtacg ggtccctctg ctatcgactg gggcgagttc ttttcatgag 420 ggccttgcct ggtgcctgga gggaacaggg tgtgggggaa aggtctgtgt gttcccccct 480 cacctcccct gctcagcggt gtggcctctg gctctgggga ggatcgggaa gccccagggt 540 ccgtgccttg gagtgggggg acagcctttt ctctgccaca gcttctgcct ttgggggctt 600 acccttccta ggagcagaac tgttgtggag gggaagagga cggtgaaggt tccgaaggga 660 agggggctgc ccccactgaa aacgaagctt ccagtcacag ccccttcatt atttatcagg 720 acccagggga tgaggtggca ggggaggggg ctgcatggag ggagtgccct caccctcgtc 780 cccagcgcct gccccctccc gaccaggcct gggctgaggc ccagggtaag ggggctgagg 840 caggccacag aggagcaaga cttgtcaggg gccagacctg ggtaggagga ttgtcctcca 900 ggcacacacg gcccccagcc ccccagcctg tcgaactggg ctctcccaga aggtccccgg 960 ctccagccca agcagggagc caggttgggg gtgtgggaag gcagaagtcc cagggatcct 1020 gggggaggct caggttgtac ctgcaggcca cagtctcctc gacagacctc ggacgaggtt 1080 gtaagtgttt taaagaaact agagcagcag agaagagaga ctcagaagcc cgtggcacgg 1140 ctttctcggc gtcccctcca gcgagggggt ctccattgct gcagttgccg gttttgtcca 1200 accaggtcag gaggctgccc ggccccctcc ccactctcaa agttgcttgt taaacacaga 1260 gtcgtaattt gtggctaaat ataactagtg tgttctcacg gaaagtataa ttcagggtgc 1320 tcattgtatg aggttatcaa caagacccat ctgggttaaa ttaaagtgat tttcataaag 1380 ggcagaagcg cccctttgcc tggtttcccc tgccttttta ttagtgacag tgttattgtt 1440 gcaattatta gaggggatca aggaaggtgg gagttgccag ggacccccag gctgaggagg 1500 gagcctccca gcccccctcc actcaccatt gtcctgctgc ccctccagcc ccctggtcac 1560 tgtcacctct gcggctggag ggctggagaa aggcccagga gcccagggaa cctccaccat 1620 gccaggctgc cttccctaaa ggccggctcc ttccccccag gcagccagtc tgggggtgga 1680 cctggagggg cagggttctc tgggaatctc tgggccaagg gatgcccttt ggggatctgc 1740 tggaataaag agtaatcggt tttccttgca ggaggttgac ccgaaacagc cctccgtctt 1800 cctgcccatg aggatgagga caggaagcca gacccgggag agaaagccca gatcagacag 1860 atgggggttg ggagggccta gtggctgaaa ctgccctgct tggggacaat gctcaggcag 1920 gaccaatcca aacgagggca ctgcttatgt ggtccttccg gagcatcctc caaggcagag 1980 cctggcttcg ggccctccct gcaaggacac ctgcctccac tccctgccag accaggcctg 2040 gctgcagagg cggaggggcg gcagggctgc ctgtctccac tgtttggcgg tgtttacacg 2100 tgtcgctgtc agggtgtctg gacagtgggg gtcgggggcc tcccgggccc agacttcccc 2160 acgctcccca agagcagcag atgtaggtct cccggctccc aaacctctga gatgctgctc 2220 tgtctgaaat catcatataa ataatcattt tttaatacaa gggggtgggg gtgtcaggca 2280 agttccatga aattgtgaat tagccgctgc tccaaataaa tgcctgcttc ggcccgagag 2340 cagccgcgct gcgcccgctg cgcccccaat aatcgtgtgc tgggtatctc tccatttgtt 2400 ccctgggcca ttagtccaaa gggcacaatt agaaacaatt tcttgacgac aaaaattgac 2460 tcttaattct tcccaccaga ggcgcagggg ggacaagtcc cagag 2505 67 247 DNA Homo sapien 67 actgagcagc tacggaatgc aaggcactgt aggaagtagg gtgagtatac tccccacaag 60 ggctcagggt caggcagggg aggtgagata aaaacccaca gccatacact agctggcctg 120 tcctgagggt tgtgaggcac aaaatgctag gagactagag aagtaagaaa tgtcttgaca 180 tgaggagaaa tcaaggaaag catggtttta gaacatgtgt gggatgtttt ttgtatcgag 240 actgaag 247 68 2458 DNA Homo sapien 68 ttgcgctgtt ttgggtgatc ttgtggtgcc gtcgcgcgcg tcatgcttgt tttctcagcg 60 gtgctatctg tgcgtcggta tgtgtgtctg ctgcacgggc tggtgcgacg cgtggtttgt 120 gctcgtgatg aatgggctgc ggcgtttgtg cctatggggc ctgttcaagt atgggggcct 180 ttgtgggcct tcggggattt ttggggggcg cgcccgttgc ttgtggttgg acggccgctc 240 tgaggatgtc aggtagcccg ttactggtgt cggaagtttg tgcaagattg agataaatga 300 ttagtaatta caggaaaact aacttgtaaa aatcttaaag acattgaatg ggttaatgta 360 ctgagcagct acggaatgca aggcactgta ggagtagggt gagtatactc cccacaaggg 420 ctcagggtca ggcaggggag gtgagataaa aacccacagc catacactag ctggcctgtc 480 ctgagggttg tgaggcacaa aatgctagga gactagagaa gtaagaaatg tcttgacatg 540 aggagaaatc aaggaaagca tggttttaga acatgtgtgg gatgtttttt gtatcgagac 600 tgaagaggct ttttaaagtg gagggaaggc aaactgaggc atagagatgc caataccagg 660 tcttgtcagg aagaacagag tccaatttgg ctgcaggata gggcatatgt aggggagggg 720 ataagactgg catgggggca gagggggact tgaatgtcag gtgacagagt caaagcttgc 780 actcaagtag gtgattgata ggtgatcttg ggggcttttg agcaggaaga gtgataaatc 840 aacattggct taggacaatc cctttggctt tggcgaaatt gtgactcagg taagggacag 900 ttgggggaga caaggatggg aagatgcatg ataaatgggc cctgagcttg gcaggcaaca 960 ggaaggcagt gcaatgtttt gtagaaatag acttagcaga gcaggcgccc agcattcagc 1020 gagaccacag attcttagcc actgtatgac ttgaaggtga tactaactcc cctgaacctg 1080 tctcatctac aaaatgggca tagtagcacc tatgtcatag ggttgcttta tggcaggtaa 1140 ttattcttgt aaagcattta gcacagctct gatgacacat ggggaatgct cagtaaatat 1200 taatgtcact aattccagtc aattccatta actggaatta attagttgga gttaggaagg 1260 aaacaggtgt cagctgggtc gactgaagga agcagagatc tcaggaagca gtacatggtg 1320 gtacagtggg agcatggcat ctgtggggga gactgtctgc agtgggatcc cacctctatt 1380 gctggccagc tgtgatcttg tacaggatac ttaacccctt tctagctcag tttctttagc 1440 tgtaaagcca gcgcaatgtt accatggagc tggtatgtga aagcaatgca tgttaagtgt 1500 gtagtatgtg cctgatacat tgttagtgcc cagtaaatgt tagttatcag gtgaggggtg 1560 ggatgtgggg ttgagtagat ttgcctcgtc cactcataga ggcaggatgt gcaaggaggg 1620 gtggagacat gcagcaaggg attgggcatg aaggttttct ccaggcccgg ggagaacact 1680 cggcctggag atattcagga gtccctggcc cagaggagat tacaactctg cagggatatg 1740 agccacgagt ggagtgtaga cataggccta aggaagcaat cagacacttc cagaatagag 1800 gacatttgct aagacagctg gcctggatgc ttcaaaaagt atcatgggaa aatatgtcgg 1860 ggttgttgta gactgaaagt gactagagtt gaaaccaaaa gaatgtatga accttgatgg 1920 gacctggttg ttgtcgttgt ttttaaagac aaacattctg gagacaattg ttgaatactg 1980 attaagggct ctgtattaga ggctataaag aagttactgt ttatattttt aggcatgatc 2040 atcttaatgt aatcatgtag aacggtgtct ttgtgctcag gaaatctatg tggtaatact 2100 caggggtcga aatgtcattc tatgtacaca tgcatggggt ggagagaata gtaaatctgg 2160 caaaatgtta acaactattc aatccaagtg gagagtatgt atctgagtat tcattgtgct 2220 agcctttcaa ctttttctgg atgtgtggaa tttttcaata taaaaaaata agaaaaaaaa 2280 gaggcctatg gaaaaactgg gaaccagtat gcaacaggaa aaggaattct ttgaaggaaa 2340 aacaggatcc acctaccaag agagcaattt caagggagag attaagcaca caatgaaggc 2400 tgcaaataga tcatcatatt tggtcactgg gagattgtgg cagcttggaa atagtccg 2458 69 894 DNA Homo sapien misc_feature (341)..(341) a, c, g or t 69 gatgataatc atataggcca atggtgactc tagatctgct cgagcgggcg cagtgtgatg 60 gatcgtggtc gcggcgaggt actccgctac tcttttactt cttttgtaaa gtattgactc 120 tggaaggcta cagtatacaa agtctcaaca tgttttttaa aagaaataag gagcaagcga 180 ctgccctgct agaaatcaca aaccgatttt tgtagaatat tttgtgcccc aggcattaat 240 ttcactgact ccagaacctg cagttcagag aatgatttct tatgatgata aaaatcgaat 300 gggatcagac gatggtttgc atttttttta attaacttgg naataggaca cctcaagttt 360 gagatttcat tttcttttag aacacagtca caagattaat ctggtgaatc cttttgtcac 420 aggttctcgg tgtgtgtgtg cgcgtctccg tgtgtgtgtg tgtgcatgtg tgtaaaactg 480 gtcacattta attgcttttt gggaccattg aatagttggg aagtaagaat tttttaattg 540 gcattaaaac ggtcctcaac tgttaaatta accaaatttg acctgtcttt aaaaaaaggc 600 ttatttgtat gattttgggc taactccccg gggaccatat taaatgacaa aaatgctcct 660 ttgggtgaca caccctacaa agtatttgct gttacgaaca taaacgccca cattcttaat 720 atctaatatt tttgaccagt gatgtcttat gctgtcatct gaacctagag aagcagtgtc 780 agaggaaacc tggtgtccat gtgtcttagc aaagggtact gatcgagggt ctgtgacaaa 840 gatggcccga gagctggggt atcatggcat agtgttctgg gtaatgttcg ccac 894 70 1335 DNA Homo sapien misc_feature (278)..(278) a, c, g or t 70 cgtggtcgcg gcgaggtact ccgctactct tttacttctt ttgtaaagta ttgactctgg 60 aaggctacag tatacaaagt ctcaacatgt tttttaaaag aaataaggag caagcgactg 120 ccctgctaga aatcacaaac cgatttttgt agaatatttt gtgccccagg cattaatttc 180 actgactcca gaacctgcag ttcagagaat gatttcttat gatgataaaa atcgaatggg 240 atcagacgat ggtttgcatt ttttttaatt aacttggnaa taggacacct caagtttgag 300 atttcatttt cttttagaac acagtcacaa gattaatctg gtgaatcctt ttgtcacagt 360 tctcgtgtgt gtgtgcgcgt ctccgtgtgt gtgtgtgtgc atgtgtgtaa aactggtcac 420 atttaattgc tttttggacc attgaatagt tgggaagtaa gaatttttta attggcatga 480 gacggttcct caactgttaa attaaccaac tttgacctgt ctttagaaaa aggcttattt 540 gtatgatttt gggctaactc cccggggacc atattaaatg acaaaaatgc tcctttgggt 600 gacacaccct acaaagtatt tgctgttacg aacataaacg cccacattct taatatctaa 660 tatttttgac cagtgatgtt ttatgctgtc atctgaaccc tagagaagca gtgtcagagg 720 aaaccttggt gtcacatgtg tcttagcaaa agggttacca tgatcgaggg tcatgtgacc 780 aaaagatgct ccagagaagc ttgagaattt gtttcaagtt gggaggaggg ttggagatac 840 aaaaatcact ctgctctaca ggactcttca gctgtctatg caagaaattc cgttttctct 900 ttcagcacct ggaaagacac agcagcccac tgaggcgata ggtgattcac taagcacaag 960 aggaatgttt tctaagcaag gcgtcccttg cctctcaaac aaatgccctc caagtttgtt 1020 agggtttcta ttcctgcaac ttgtggtatc aaaaccactt cctgaaattg tcaaagcact 1080 gccaaaataa atgtttttcc cccttctaag aaaaaaaaaa tgacagtgct catatttgac 1140 acttgtgtat tggactctct tttgaatgaa taaaaaggaa aaggggtttg gtgtaattcc 1200 tgatggggtg cgtgttgttt ttcatgccat ggtttgtgaa ttttaattgt ggtttcccat 1260 ttcgttgttg taactgggca gaaattaaaa aagaaaaatc aataaaaata caaagaaatg 1320 gttaaaaaaa aaaaa 1335 71 137 DNA Homo sapien 71 cgggcaggta cgcacaagca ggcccagctg ggagacgcta ggataactaa gacctggtca 60 gcgccctgag gagtcttgtc tggataaagg gagacacaca ctagcttgga cttatgcgtg 120 cagcggagct gtgtaga 137 72 694 DNA Homo sapien 72 ccgcccgggc aggtaccaac cccagcacac cccaacagcc tttcctcggc ccctcctcag 60 gcctcctaat tactctttct cagcctggag tgtggggccg ttaccgtcct cttccccctt 120 ctccttccat actgcactta accttgctgg aagacttaat gatggagatt tagggcaatc 180 tgtggctgct tggacccttc cctggaccaa aggaacttaa aacccaaacc tgacactgga 240 atgaaatcca agtttttaaa tatcaccttt caatcactca cagatctcac tctatcttaa 300 aatactcagc ctcactcctt aatgagtgct tgctgaaggg agaaaattcc attttaaaaa 360 cgtattcact ttactgatta ctgtgcaatt tgaattaagt cacgattctt tagtaaatgg 420 aggtgagaat ctcagattca aattgtcaga gaccatgatt tagaagtcta ccaaacaccc 480 agtttccttc cactgtttta gggtaacagg aaaacatgag attggggtgg tgtccgctat 540 taaatggaac cacacatcat gaaattcaat tctcatgtta agacattctg tattgtggga 600 tgtcaaaagt atttcccaaa ctttcgtttg acctgcagag ttggagatgg cttacctccc 660 tataacttca agtttgtttc acaaagcttg gcgt 694 73 8095 DNA Homo sapien 73 tttttttttt gccacctaga gatgataatt tattgtttta ccatgactca gaagagaaac 60 aacataaaga gaatatttca aatccccaca atttccttcc tcaacctcac tactcttaac 120 atttctttat cagacgccac tggcttccta aaatggacca ctgactatgt atgtgtacac 180 atttcattat gctgcctttt ctcttatgat taaaacttta gccctcattc gaggtttcca 240 atggttactt ttagtggagg agttccctag cttttaaaaa accacttttc ctctaagatt 300 ccattattta ttgaaagaag tctttctaga aatgttaagg aggattttaa atgaacacat 360 tcaattaaaa aaaaaatcac gtattgaaca tctaccaagc atctggactc ttcggaacct 420 agtaaaatga aaaaatccag ttttaacaac agtaacttca ttctgcgggt atacagagac 480 aagcacgttt cttcttttgg tctaatttat tctaaacgaa gaagctggga actgacaaaa 540 caggacaggt tgtttttaat ccagtctaca aataaacaag acaatgcctg agttagccct 600 ctatatagat ttaggcttat gctgacctcg ttgtaaaatc tgtatttaac taaaagttaa 660 taaaaataca tatgttcatt ttaaaataat tactgatttt gcttggctat cccacccctt 720 acccccaaac tcatatattt ttaggacaag attttcctgc ataaccacaa cctgtctcct 780 cccaccccac ccccatcata gatgttttca aataagaacc cctgcgatca gcagaagcat 840 ctctaatcta acatgctttg tccttgctag ggcaggctaa aagctttaaa aagcaaccgg 900 atgctcttct ctggttgagg tgaggggaag gcgctcgggt accaacccca gcacacccca 960 acagcctttc ctcggcccct cctcaggcct cctaattact ctttctcagc ctggagtgtg 1020 gggccgttac cgtcctcttc ccccttctcc ttccatactg cacttaacct tgctggaaga 1080 cttaatgatg gagatttagg gcaactgtgg ctgcttggac ccttccctgg accaaaggaa 1140 cttaaaaccc aaacctgaca ctggaatgaa atccaagttt ttaaatatca cctttcaatc 1200 actcacagat ctcactctat cttaaaatac tcagcctcac tccttaatga gtgcttgctg 1260 aagggagaaa attccatttt aaaaacgtat tcactttact gattactgtg caatttgaat 1320 taagtcacga ttctttagta aatggaggtg agaatctcag attcaaattg tcagagacca 1380 tgatttagaa gtctaccaaa cacccagttt ccttccactg ttttagggta acaggaaaac 1440 atgagattgg ggtggtgtcc gctattaaat ggaaccacac atcatgaaat tcaattctca 1500 tgttaagaca ttctgtattg tgggatgtca aaagtatttc ccaaactttc gtttgacctg 1560 cagagttgga gatggcttac ctccctataa cttcaagttt gtttcacaaa gctttgaaaa 1620 gtaaaacaga taatttcatt ttcagataat aaaaaatctg aatagcaaaa taattgcttt 1680 taaatgtagt gtgtccactc taaaaaaaaa aaccctaaat ctatgttaga aaaacttttc 1740 aaataatgcc ttttattaaa ttctccagta gtagttgaaa taaaaatcta ccctaatttc 1800 tatgaaatga tctatttata tcactgactt ttctttttct ctgattctat atttcattta 1860 acaatctgca gactttcacc ccatttccca gatgggaaaa ccctagcccc ctcgtatctc 1920 tgagaagttg ctcagagtag gacacagaga aatatggccc ccaccctggg aagtactgct 1980 gtcactgttt aagtgtattt cagttctgtt actccaattc atacacacag tcttccatga 2040 ggatggtagg atgaacctgg ttagctggct ttggataagt agatcagcat gactacctgg 2100 aataaaagtg actgactcta ggataaaaat taaaaaaaga ttctttcaca gcaacgagtc 2160 tttgcaaaac ctctctccta ataatcacaa accaggggaa gaaaagtggg agcagggaac 2220 acaggaacac agccaaaggg aatattgcaa aatgcttccc gagcttcatc agacagactt 2280 cttgcaatgc cacgactgga tgcatctgca cacaattccg ggaaatgccc accttgctgt 2340 tctcctatcc ccaattttct ttctttcttt ctttcttttt ttcttttttt tgagacagag 2400 tctctgttac ccaggctgga gtgcagtggt gcaatctcgg ctcactggca acctctgcct 2460 cccagattta ggtgattctc ctgcctcagc ctcctgagta gctgggacta caggcgccca 2520 ccaccacgcc cggctaattt ttgtattttt agtagagaca ggctttcacc acgttggcca 2580 ggctggtctc aaactcctga cctcaagtga tccgcccacc tctgcctccc aaagtgctga 2640 gattacagga gtgagccacc gtgcctggcc agtcctatcc tccccccaac cttttttttt 2700 tttttgacat ggagtctcac gccatcaccc aggctggagt gcagtggcgc catcttggct 2760 cactgcaacc tccgcctccc atgttcaagt gatcctcctg cctcagcctc ctgagtagct 2820 gggactacag atgaagacaa gcacctgtgg tgcccctcac tgcaagaagt cagggaggca 2880 ttccacagcc tgggtgccca cagtcctgcc ctgtaccctc tggggccctt ttggcacggt 2940 ggcagcgctt ccagatttcc tttcagaaag atgcagtcct tccgcagctg ggccatgcag 3000 atctcctggc atccaacttg ttggaaacag tggccctctg ctcaatgatg agactgggga 3060 ggggaaacag gaggacattt caaggaaagg atggagcgtg gatatgaatg ggaagcgggt 3120 ggtgggggag ctcatcagca tcctcagagg ggctcatgcc cacgctgcaa cacagaatgg 3180 gacttgccag atgtttgtag tcgactctga gtgccccgtg ctgagaaacc tgaaagcaca 3240 cccacctatg gctgcgcgtg ttgcacgctc aaggctgagt tcacatagtt ctgtagcctc 3300 ctcctacacc aagtcaggtc ggccctgtgt gaccagtaga agagatggga tgtcactttc 3360 gagggtgctt ccaggcgagg ctggcctgaa tgagaatgag gagcaggacg ctccccaaga 3420 gattgccttg gacatcagcc tgggccacat ctacaagttc agacccattc agcagctaaa 3480 ttccaggagc atcacggaga atctccggcg agctcagcac caaggcaggc actgtgctgg 3540 ctgtgggccg gatgctacag aaactgtgtt atcggacacg ggtcctgatc taggccccaa 3600 gagagagttc ttgtacaaga aagaattggg gccaggcatg tttctggcgc tgtgtgccca 3660 ggcccagccg ggggcctaca ctgatgagaa cctcatggga ctgattgagc tgctgtgccg 3720 caccagcctg gacgtggggc tccgcctgct gcccaaagtt gacctccagc agcttctcct 3780 cttgctcctg gagaacatcc gggagtggcc agggaaggcg cttccttcca ggacagatgt 3840 cccacggctt gcagatggct gggcccagga gacggtgcta gcccttcctc tgagagaagg 3900 ggtgcaggct gccgccaccg tgcccatcct cctgtacaac ctggaggatg gcttgtcaga 3960 ccatcccctg gaccagggcc ccgctgccct gcccggcggc cctgcagccc tgcctcggct 4020 ccagctctca catcgccaaa gaagcccaag atacaggcac ctggggaaac cgttgacggt 4080 ttttgctgtt ccagttttgg ctgcttctca agatcacgaa gcccagggca ctctgcaagg 4140 gtttctgcaa gttcagcagt tcatcgctgg agggcgcttc cttccaggac agatgtccca 4200 cggcttgcag atggctgggc cccaggagac ggtgctagcc cttcctctga gagaaggggt 4260 gcaggctgcc gccaccgcgc ccatcctcct gtacaacctg gaggatggct tgtcagacca 4320 tcccctggac caggggcccc gctgccctgc ccggcggccc tgcagccctg cctcggctcc 4380 agctcccaca tcgccaaaga agcccaagat gcaggcacct ggggaaacgt ttcccactga 4440 ctggagcccc ccgcccgtgg aattcctcaa cccgagggtg ctgcaggcca gtcgggaggc 4500 cccggcccag aggtgggtgg gtgtggtggg cccccagggc ctgaggagac tggctggtga 4560 gctgcccgag gagttggagc aggaacacct ggacttggac ccgaagaggg gcctggcctt 4620 gccagagaag ctgttctgga acacgtcagg cctgagccag caggctgcgg ccccagagtt 4680 ttcctggggg ggctcaggaa gctacttcaa caacctggac tacttactgc aggagaagag 4740 ggaacaggcc ctggagcagg agcgagagag gctgcttctg caggagtgtc tcaatctcaa 4800 ctccttggat cttgatgaag aggaagtgcc actcacaccc gagcacagaa agaggcaaga 4860 gagctctctg gggccctttc ataagggtac caatcctatt catgaaggct ccaccctcat 4920 gcctcatcac ctcccaaagg ccccacttcc taataccttc accctggggc tttccttccg 4980 gagacaagca gtaaataaga tcagtgaagt tgtgctgcaa gggctcctga gaaaggctaa 5040 cgctgggggc ataaggagtg ctgggaaagg tgtgggctct gatgatgtgg gctctaatca 5100 tgtgggcttt gatgatgaag gctctgatga tgaagggatg ctggtggaaa agtactcagt 5160 gtccctgcag accatcccgc cggtccatcc aggtgagact gtgtttctgc ccaggtgtca 5220 ccccctgcca tgcatcctgg actcctcact cctgaagcca cgcagccacc tggaagggct 5280 gttcctcagg cagtatgctg agcattggga cctcaaggat gaggaagatg cagtctctgc 5340 cctagaggag cttacagcag caggaagttt ctgtcatagg acagacccag ggctcaccaa 5400 gactcaagca gatgatgaag cctggggctc actggcccaa tcagcgtatt cagactggct 5460 ggctgcttat gaggctcttg ggccagggct gcctgctcag tgggcagctg actctagctg 5520 ctgcaaaatg cctttcactc aaaggttttt gcttttgcca atcccctccc tcacatgcct 5580 tgaaacaagc actttcaaag acaaagacat aaacaacaaa agggtgcagg ctgagttgcc 5640 aacttacagt gtcattgggc cgattcaggt tcttgactgc tgcacaaaag aatttgagag 5700 caagtacaaa gcaaaagtag gtaaagaagt ttattgcaaa gcgaagatct cctgggaggc 5760 ccccgtggag aagaagactg agtgtatcca gaaagggaag aacaaccagg tgggtgcttg 5820 gacgctgctc ctggtgctgc cttcacccca ggacgtctcc tcccattctg gccctcgcgc 5880 tctcactaac cggacacctt tctgccccca gaccgagtgc ttcaacttca tccgcttcct 5940 gcagccctac aatgcctccc acctgtacgt ctgtggcacc tacgccttcc agcccaagtg 6000 cacctacgtc aacatgctca ccttcacttt ggagcatgga gagtttgaag atgggaaggg 6060 caagtgtccc tatgacccag ctaagggcca tgctggcctt cttgtggatg gtgagctgta 6120 ctcggccaca ctcaacaact tcctgggcac ggaacccatt atcctgcgta acatggggcc 6180 ccaccactcc atgaagacag agtacctggc cttttggctc aacgaacctc actttgtagg 6240 ctctgcctat gtacctgaga gtgtgggcag cttcacgggg gacgacgaca aggtctactt 6300 cttcttcagg gagcgggcag tggagtccga ctgctatgcc gagcaggtgg tggctcgtgt 6360 ggcccgtgtc tgcaagggcg atatgggggg cgcacggacc ctgcagagga agtggaccac 6420 gttcctgaag gcgcggctgg catgctctgc cccgaactgg cagctctact tcaaccagct 6480 gcaggcgatg cacaccctgc aggacacctc ctggcacaac accaccttct ttggggtttt 6540 tcaagcacag tggggtgaca tgtacctgtc ggccatctgt gagtaccagt tggaagagat 6600 ccagcgggtg tttgagggcc cctataagga gtaccatgag gaagcccaga agtgggaccg 6660 ctacactgac cctgtaccca gccctcggcc tggctcgtgc attaacaact ggcatcggcg 6720 ccacggctac accagctccc tggagctacc cgacaacatc ctcaacttcg tcaagaagca 6780 cccgctgatg gaggagcagg tggggcctcg gtggagccgc cccctgctcg tgaagaaggg 6840 caccaacttc acccacctgg tggccgaccg ggttacagga cttgatggag ccacctatac 6900 agtgctgttc attggcacag gagacggctg gctgctcaag gctgtgagcc tggggccctg 6960 ggttcacctg attgaggagc tgcagctgtt tgaccaggag cccatgagaa gcctggtgct 7020 atctcagagc aaggtaaagc tgctctttgc cggctcccgc tctcagctgg tgcagctgcc 7080 cgtggccgac tgcatgaagt atcgctcctg tgcagactgt gtcctcgccc gggaccccta 7140 ttgcgcctgg agcgtcaaca ccagccgctg tgtggccgtg ggtggccact ctggatctct 7200 actgatccag catgtgatga cctcggacac ttcaggcatc tgcaacctcc gtggcagtaa 7260 gaaagtcagg cccactccca aaaacatcac ggtggtggcg ggcacagacc tggtgctgcc 7320 ctgccacctc tcctccaact tggcccatgc ccgctggacc tttgggggcc gggacctgcc 7380 tgcggaacag cccgggtcct tcctctacga tgcccggctc caggccctgg ttgtgatggc 7440 tgcccagccc cgccatgccg gggcctacca ctgcttttca gaggagcagg gggcgcggct 7500 ggctgctgaa ggctaccttg tggctgtcgt ggcaggcccg tcggtgacct tggaggcccg 7560 ggcccccctg gaaaacctgg ggctggtgtg gctggcggtg gtggccctgg gggctgtgtg 7620 cctggtgctg ctgctgctgg tgctgtcatt gcgccggcgg ctgcgggaag agctggagaa 7680 aggggccaag gctactgaga ggaccttggt gtaccccctg gagctgccca aggagcccac 7740 cagtcccccc ttccggccct gtcctgaacc agatgagaaa ctttgggatc ctgtcggtta 7800 ctactattca gatggctccc ttaagatagt acctgggcat gcccggtgcc agcccggtgg 7860 ggggccccct tcgccacctc caggcatccc aggccagcct ctgccttctc caactcggct 7920 tcacctgggg ggtgggcgga actcaaatgc caatggttac gtgcgcttac aactaggagg 7980 ggaggaccgg ggagggctcg ggcaccccct gcctgagctc gcggatgaac tgagacgcaa 8040 actgcagcaa cgccagccac tgcccgactc caaccccgag gagtcatcag tatga 8095 74 435 DNA Homo sapien misc_feature (86)..(86) a, c, g or t 74 ggatgttcga tcactatagc cttgtgcctc tagatgctgc tcgagcggcg cagtgtgatg 60 gatgtcgcgg ccgaggtact tcccanggtg ggggccatat ttctctgtgt cctactctga 120 gcaacttctc agagatacga gggggctagg gttttcccat ctgggaaatg gggtgaaagt 180 ctgcagattg ttaaatgaaa tatagaatca gcagaaaaag aaaagtcagt gatataaata 240 gatcatttca tagaaattag ggtagatttt tatttcaact actactggag aatttaataa 300 aaggcattat ttgaaaagtt tttctaacat agatttaggg tttttttttt tagagtggac 360 acactacatt taaaagcaat tatttgtgct atccagattt tttattatct gaaaatgaaa 420 ttatctgttt tactt 435 75 608 DNA Homo sapien 75 ggggggcata tttctctgtg tcctactctg agcaacttct cagagatacg agggggctag 60 ggttttccca tctgggaaat ggggtgaaag tctgcagatg ttaaatgaaa tatagaatca 120 gagaaaaaga aaagtcagtg atataaatag atcatttcat agaaattagg gtagattttt 180 atttcaacta ctactggaga atttaataaa aggcattatt tgaaaagttt ttctaacata 240 gatttagggt tttttttttt agaggggaca cactcccttc ctactcccca acaaggggct 300 cactatcccc aaagaaggag ctgtggggga cccacgacgc agccccggta cgggattaca 360 gcatattctc atctcgggcc ccgaggctgc ctgtggggcg aggggagacc tcccatcacg 420 gagacagatc acagaccacg agtgcctttc ccggaccggg acgtggcctc cagagcaggc 480 accagctctt tccctctcta gacagaaata ttttggtaag gttctggggc agggagggag 540 catgaagtac gaggaaaact tgaattccag attcttaatg caaagtattt atcatttcta 600 ccagaaat 608 76 727 DNA Homo sapien 76 gatgattcga ctcactatgg gcgaatgtgc ctctagatgc tgctcgagcg gcgcagtgtg 60 atgggtcgcg gcgaggtact tcctagacac tgtagtttaa aagaataatt tcctgtagaa 120 aaacctaatc taataggacc tactcataat ttggcaaaat catcctcata attccatgct 180 actgaaatgg gggtgtaata aagaaaaaat catttgttta ttcatttaac agggtttatt 240 aaagcaccaa tatatgccca gaactttgca gtgcactgga agttcagaga taagaaagcc 300 acagtttctg ccatcaaaat gctaggaatc tagaggtctc aaacatcaga ggtcccttca 360 aactatgtct accaggaaaa taaaatacct gatttcatcc ctgcaaacaa ctctatacag 420 acagaaatgc ttcctagctt ggaaactata gaaaattgaa catgaaaatg agagcaaaga 480 ttctacatca aaatggcaat gatccaatca gcccagtcaa ggctgagtgg gttgaatggg 540 gacttcgagt ttggattcaa tgctttgaac ttcatagctc cagagaagct gtgcaaaaag 600 gggggattct agggaatctg aggaagattg ttggagaaac cagctttctt cttgtctcct 660 aatccctgct aagattgata ccagtcaagg agctgagtta ctttcatttc attatgttga 720 ccaagag 727 77 3052 DNA Homo sapien 77 ggaggtggag gggaggagtg cctgcatggc catgggattg ttcttcattc cctttctcaa 60 ctgcacccag cagcagtggt ttttgctagg ccttttgaag acagcaggaa tctgggagaa 120 ggaacatcat cgtctttcac agcatggaaa catcaatctt attccagaga agggaagaag 180 tccccaaagg tatgtccggt ttaacagttt ctcaagtggg ccaggaagtt ctttttcatg 240 ttctgggctc aatcgtgatg ctttgatttc acttggtatt ttacttttag ttttgtctct 300 aacatctgga gcaaagatca gaagacctga gttccagatt tattctgtga ctcaatcact 360 gcttcaatca ctgagggacg tggtatgatg ttctttgctc tgagcttctg cttcttgatc 420 taaaaagaca ggtggttgtt ctgggtgatc aaaatctctt cttgctctgt gtatcttaga 480 atccatgaaa ttatgtctct ttgcatctat gataacaaat caaaatatga atcacaattt 540 tcttacaggg ttgctgaggt taaagccgtg aaagcctggg aacaaatctc cccagggaag 600 gtttaagcaa gcattaactc tttcttctgc aagttccccc attcattgct agggtgttgt 660 ctgatagcca ccatgcacag ttgactttcc ttgggaaatc atgagtcttt tatttttgca 720 atttggcttt atctcctaca catcatccag atggtgcaac atctggtact atatgtccaa 780 tggaattgcc acaactcagc cactgagatc caacattcct gcctctcttc attccaagat 840 tccttctgtt ctttattgtg gtagacaaga gcaagcattt ttatttgcag agatgtactt 900 atttaaaaag caattgtgaa agcatttgat ttaataatta ggattgtttc tccacgattc 960 tttttctgaa aaaaaatttt tttggtgtaa atttagagtt cataagtaac accaaagact 1020 gagacaatga agtccatgca tactgtaaaa aaataacata aataacagtc cctagtatgc 1080 atcagtcatt gtactagagg ctttgtgtgt acattgattg tctcacttga aaatcaaaac 1140 acggcagaag agtcaaatgc ttttgaatgt gctgaaactc aaattttctt ccaggtcatc 1200 tctgtatgat tcctctttta cactgccatt actggcttct aaaaccacta aagctatgca 1260 gatagcctgg tcctaacatg ttctaaactg ggcattagtg aggggctgcc tgctggcttg 1320 tttaggggcc agttggctca gtttggaatg gtttaatatc agcaacaata gcattgggtt 1380 gatttgaata taaacaactt agactttaaa agttcatcct gaaaaacaag ccttcaagga 1440 caagtgagga catgaagcaa attcctaagg atgcctgggg ttcaggaagc aaagaagaat 1500 ctttggttat tcatgaaaac caaataccag ctatgtggca tcttctggga aagcacaggg 1560 gtgggagaat cctggggtgt gtttggcagc actgtccaaa gtacagttga cttcttaggc 1620 tgctgaacaa atttcttctc ttgccccagg agaatttgat ctgcaggttc ccataagtag 1680 agtaacatct ttctcttgaa ataggtgctg tgtcaaagtc tgtatcataa gcttctcttg 1740 gtcaacataa tgaaatgaaa gtaactcagc tccttgactg gtatcaatct tagcagggat 1800 taggagacaa gaagaaagct ggtttctcca acaatcttcc tcagattccc tagaatcccc 1860 cctttttgca cagcttctct ggagctatga agttcaaagc attgaatcca aactcgaagt 1920 ccccattcaa cccactcagc cttgactggg ctgattggat cattgccatt ttgatgtaga 1980 atctttgctc tcattttcat gttcaatttt ctatagtttc caagctagga agcatttctg 2040 tctgtataga gttgtttgca gggatgaaat caggtatttt attttcctgg tagacatagt 2100 ttgaagggac ctctgatgtt tgagacctct agattcctag cattttgatg gcagaaactg 2160 tggttttctt atctctgaac ttccagtgca ctgcaaagtt ctgggcatat attggtgctt 2220 aataaaccct gttaaatgaa taaacaaatg attttttctt tattacaccc ccatttcagt 2280 agcatggaat tatgaggatg attttgccaa attatgagta ggtcctatta gattaggttt 2340 ttctacagga aattattctt tcaaactaca gtgtctagga agtaccttgc acaaaataga 2400 cacaggatgc ataattgttg attaattagt tcattttaac ctatacacct tggggttatc 2460 tagttatgtt ttcatgaaaa ctagggcttt gtaatatcaa tgtcatgtct aataagccta 2520 aatttccagt tctaaaaaca aagttattca acaacacttt ctcaatttga tgtgtttttc 2580 ttttcctgaa ataatttttt ttcttaagct tttgatattt gcttttgtgc tgacatttga 2640 tagtcaaaac tcaaacgatc tcaagtactt ctttctcagc tcaataggat catgtttcgc 2700 ttaacatttg tgaagttgat ttatctaatt cattttgatc ttgctaaaat atgaccttta 2760 aaatttttca tgtcacattg tgacccagaa agaccaaata catacatgag atcatagttt 2820 tacctgataa tatcactcct agtttgatga tggaattaat ttgtcaatat ttcatggagt 2880 tctgctgaaa cgattgcaat ttcttgggca agtttcagaa cgaccagcat atctgtggtc 2940 atgtcatctt gggtcatgtt aaccagttcc attggattat catgctgttc ccttgtctga 3000 caaaaggatc tttgtgaaag cacacactgt ttcttcccat aactcacatt ca 3052 78 416 DNA Homo sapien 78 gccgcccggg caggtagcct ttttctctcc agccttgaat tgttccctgt tggcttccca 60 agggcccatc tgctggtaca gtccacactt ccaaagccaa gacccgagag ggctttcact 120 gccccaagcc tctctcctgt gaccttggga ttctgtcttg gcagaatcct ttgtcagcgg 180 ctcttgctct gtccttcctg tttggccaca gctctttcaa tcaatgggta ttctagaacc 240 gcaggatgtc agagctggaa gggacgcgat accggtttac acaaggggaa actcctcgag 300 gctctgggag ggacggaggg ttttggtgac agagcgagag ctaaaattga ggattcctga 360 atccagatct tgcctcccat cagccatctt tctcccaata aatttatgtt atgtgc 416 79 1451 DNA Homo sapien 79 taaaaacttt gtcccgatcc atccagaaaa gagtaggtag ctgcatcctg acagcctggc 60 aaagtcaaga aagttgaagg agaaacatac ctttggagag ggggttttct ttaaaactag 120 tgttaagaaa tgcttaggga tttttttttc ttatttttca taactaaagc tttcacccag 180 agccggctct gtttgcactt tgctgccgac attgcaaact ttttggcagg gtgggagact 240 gagtctcatt ctgtcaccca ggctggagtg cagtggcccg atctcagctt actgcaacct 300 ctgccctcca gggttctggc aattccgcct cagtctcctg agtagctggg attacaggca 360 tgcgccacca cacccggtta atttttgtat ttttagtaga gaccaggttt catcatgttg 420 ggcaggatgg tcttgaaccc ctgacctcag gtgatctgcc catctcggcc tctcaaagtg 480 ctgggattac aagtgtgagc catcgcgccc ggcctgcaaa cttttttgta ggtatttctg 540 gtaaacaaat ccttaggtta tctttgctgt ggttgtggtt tggctttagt catgatttca 600 aagtagaaat agctaggcat tattttttga aatatatgac ctatatgtag tcaagaatcc 660 actgaacaga gggaagcaaa ccttttggaa actggctttt gggcagacag taaacgtcca 720 gtttgatgct ggaagcatga acagcttcat caggtaggta ctcctcaact ctgatgagtt 780 tgtcctttca gcctaagggg gtggaaggga gttgtttgag aatagcaaat acgcatgttg 840 attgcgagtg tgtggagaca aaggcagttc ccaccacagt taggtcctgg ccgttgtgtt 900 gtttcctcgc ctgcgatgct ccttgtacgt cctcaccctc ctctcccgcc tctgccttct 960 gctgggtcaa aggtggcctt tttctctcca gccttgaatt gttccctgtt ggcttcccaa 1020 gggcccatct gctggtacag tccacacttc caaagccaag acccgagagg gctttcactg 1080 ccccaagcct ctctcctgtg accttgggat tctgtcttgg cagaatcctt tgtcagcggc 1140 tcttgctctg tccttcctgt ttggccacag ctctttcaat caatgggtat tctagaaccg 1200 caggatgtca gagctggaag ggacgcgata ccggtttaca caaggggaaa ctcctcgagg 1260 ctctgggagg gacggagggt tttggtgaca gagcgagagc taaaattgag gattcctgaa 1320 tccagatctt gcctcccatc agccatcttt ctcccaataa atttttgttt tgtgcaaggc 1380 taaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 1440 aaatgagcgg c 1451 80 1336 DNA Homo sapien 80 ccgaggtaca aaggctttga ggtccatgga ctatacttgt ccccatttat catcccaggt 60 ggtgctttga ccctgccata ccctggctat taagataaaa agatttgtgg acattaaaat 120 tatgaatatg tcagtaataa tccagcacac attgaaatat tgacacagat taccataatt 180 tgtgcaacat cttataaaca atgtcatttc catagtagtc taaggcttca ccagcctggc 240 ccactgtatc tagactttag gttcatttta ataattatgc tttccttctc tgtatcattt 300 gggaagttga taaatatcac ttccttagat accttcattc agtgatatat ctggctttta 360 caattaaatt ggaaaaggta agtttctctt tggtgggttg agagttggac catcaattct 420 aatctacaaa aggaaattca tgatttcact ctgacgccta ggatctagcc aaggctggtc 480 tgcagtatca aatgtccaaa ctcatctact attagccata ttttgtgagt cgtttgtcta 540 aactttgtca aaaatgcctt tgccatgatt ttgttgctat ctggatttca aacatggaca 600 gttaggaaga tgtgcattga agtaggaaaa tttgttcaga ttgctgtatt tattttttac 660 attaaacatg gacatgtctc tcaaaaaaaa aaaaaaaaaa ggctgggggt actcggggcc 720 atagcggttc ccggggggaa atgggtaccc gcccacaatc ccacacaaca accgagcacc 780 cccccccacc cccaaccaca atacatataa cacaaacctt acataaaaaa cactaacaca 840 acaaacacac aacaaaaaaa acacaccaac acacaaatca ccataacaca acaacataca 900 ccacaacaca caacaacccc gcccaccccc caccactcaa caccaccaca caacacaaca 960 cccgcaccga cccccacaca cccccgcccc acccaccaca cgccccacca caccaccacc 1020 cacacacaca cacactccca ccacacacac acaccccccc caacacccac ccacccccac 1080 aacaccaccc caccacacca cgcacccaca ccccacacac cgccaccacc acacccccac 1140 gaccacccac cacacacacc cacacacccc cacacccacc cacaccccca cccctcccca 1200 ccaccacacc acacccaaca tctcactcca ctctctcccc ccaccaccca cactcaacca 1260 catcatcact cccctctaca cacaacaaca tcaccaacac tccacctgca cacacactca 1320 ctccccacac atcacc 1336 81 1605 DNA Homo sapien 81 atttataagg cccttcaaat ttgtggcttc ctttctcata cttctcaagt ataatgaaag 60 ggggagaaaa accccaccat caacacaaaa gaaggctata aagactgtgc accttttaac 120 aagtcaattt gtagtcagtc cctgggcctg tctttttttt tttttaattt tgaagctacc 180 tgaggtttag aattccttca gccctagctg cttttattct gctttttatt taaacaaaaa 240 gagggggagg atctgaagga aactagtttt ctgtacaaag gctttgaggt ccatggacta 300 tacttgtccc atttatcatc ccaggtggtg ctttgaccct gccataccct ggctattaag 360 ataaaaagat ttgtggacat taaaattatg aatatgtcag taataatcca gcacacattg 420 aaatattgac acagattacc ataatttgtg caacatctta taaacaatgt catttccata 480 gtagtctaag gcttcaccag cctggcccac tgtatctaga ctttaggttc attttaataa 540 ttatgctttc cttctctgta tcatttggga agttgataaa tatcacttcc ttagatacct 600 tcattcagtg atatatctgg cttttacaat taaattggaa aaggtaagtt tctctttggt 660 gggttgagag ttggaccatc aattctaatc tacaaaagga aattcatgat ttcactctga 720 cgcctaggat ctagccaagg ctggtctgca gtatcagatg tccaaactca tctactatta 780 gccatatttt gtgagtcgtt tgtctaaact ttgtcaaaaa tgcctttgcc atgattttgt 840 tgctatctgg atttcaaaca tggacagtta ggaagatgtg cattgaagta ggaaaatttt 900 gttcagattt gctgttattt attttttaaa ttaaaaatgg aaatgtaaaa aaaaaaaaaa 960 aaaaaaaaag gctgggggta ctcggggcca tagcggttcc cggggggaaa tgggtacccg 1020 cccacaatcc cacacaacaa ccgagcaccc ccccccaccc ccaaccacaa tacatataac 1080 acaaacctta cataaaaaac actaacacaa caaacacaca acaaaaaaaa cacaccaaca 1140 cacaaatcac cataacacaa caacatacac cacaacacac aacaaccccg cccacccccc 1200 accactcaac accaccacac aacacaacac ccgcaccgac ccccacacac ccccgcccca 1260 cccaccacac gccccaccac accaccaccc acacacacac acactcccac cacacacaca 1320 cacccccccc aacacccacc cacccccaca acaccacccc accacaccac gcacccacac 1380 cccacacacc gccaccacca cacccccacg accacccacc acacacaccc acacaccccc 1440 acacccaccc acacccccac ccctccccac caccacacca cacccaacat ctcactccac 1500 tctctccccc caccacccac actcaaccac atcatcactc ccctctacac acaacaacat 1560 caccaacact ccacctgcac acacactcac tccccacaca tcacc 1605 82 952 DNA Homo sapien 82 tatatatagg cgcatgggct aaatgatcat gctcgagcgg cgcagtgtga tggatcgtgg 60 tcgcggcgag gtaccaggtg aagtgattgg cctgcagtta gggctgtgtt gtgcaaaaat 120 cacttgtttt ggggtgttag aaccacattt aggcgagaag atcacttttg gggagcttgg 180 gaactgaggc aggccgcagg tgcagcagag gcatgagctt gcccgggccc gccctcttgt 240 ctatgctcat ggagtgaagg gggggccagc ggaatggccc aaacaactga tttgtttttc 300 tttttttaaa tctttttcag acaaatacca ttgtgtttaa gcgaaatgtg tgtataatgc 360 caaatcactg taccccacaa ccctgcacac ctctacactg gactgtaatt tcttgttcct 420 agtttgtctt gctagactgt aagctccgtg agagcaggga ccgtgtctgc ttgttgagtg 480 ggctttcccc tgtgcctgcc agcatgcctg gcatctagca ggtcttctgt aaagatggga 540 tgagtttgta aaccctccag cctcaggagt ggctccatcc tctgaggctc tggggccctc 600 tggcaggcta gtcatttttc tgccatgtac gtacaatgct ttattttcat gttgtatttt 660 cctttctagc cagtaagcaa agctcctact ggagcaagtt tctttgtggt gttatctctg 720 tatcctttca tcagggccag gccagagtaa gtaggtgctt cgaaggtgtt tggtaatgaa 780 tgactttggt accccgccca gtctggctca ctgtctgcgg ttgtctaatc tagatgaagc 840 ccgattcgaa ggggggattt ccggagtgct tggggttgga aaaatctctt attgccgggt 900 actcattggg tcgggcgggg gcgagtgggg actgctggtc ggggatgtcg cc 952 83 1933 DNA Homo sapien 83 cacccttttt gatagcatgt tatgaggctc accaaggtct atcctctggc agtatccctg 60 gcctgttctc cccatctccc ctgccctctg ctcaccagtt ccctaaatgt atcttgatct 120 cactagccct acagactgtg cacagagctg tttctacctc cagtgacatg cttccgccca 180 ggcttctccc cctcccgcct caatcttccc ctcaccaact taaggtctta ggggcccttc 240 taggaggcag tccccaactt ccagagccag ggtataggct acttctatgt gtcccatggt 300 actgccacag aagagtctca gctctctcca ggattcagtt ctaaggtcag tgcctaagat 360 aaaaatggag tgtaattaaa attcctctta gaaatctaag gaaggtgccc tattgaagac 420 caacatcttg aggtcccatg tagtcatttc ttgcccatgt gggaacacat tactgtttgg 480 ttgagtacca ggtgaagtga ttggcctgca gttagggctg tgttgtgcaa aaatcacttg 540 ttttggggtg ttagaaccac atttaggcga gaagatcact tttggggagc ttgggaactg 600 aggcaggccg caggtgcagc agaggcatga gcttgcccgg gcccgccctc ttgtctatgc 660 tcatggagtg aaggaggggc cagcggaatg gcccaaacaa ctgatttgtt tttctttttt 720 taaatctttt tcagacaaat accattgtgt ttaagcgaaa tgtgtgtata atgccaaatc 780 actgtacccc acaaccctgc acacctctac actggactgt aatttcttgt tcctagtttg 840 tcttgctaga ctgtaagctc cgtgagagca gggaccgtgt ctgcttgttg agtgggcttt 900 cccctgtgcc tgccagcatg cctggcatct agcaggtctt ctgtaaagat gggatgagtt 960 tgtaaaccct ccagcctcag gagtggctcc atcctctgag gctctggggc cctctggcag 1020 gctagtcatt tttctgccat gtacgtacaa tgctttattt tcatgttgta ttttcctttc 1080 tagccagtaa gcaagctcct aatgagcaag tttctttgtg gtgttatctc tgtatccttt 1140 catcaggcca gcccagagta agtagtgctt cgaaagtgtt tggtaaatga atgaattatg 1200 gtaacccagc ccagttctgg catcactgtc tgcaggttag tctaattcca gatgaaagcc 1260 ccagattcga aaaagggaag attattcaga agtgcatatg gttgtataag aaaaaaaaat 1320 ctcattaaat agacctgagt aaacttcaaa ttttgatgat ctggccatgt cggagctgaa 1380 gcttaccagc tctctaaagc atttgctagg gaatcatgca gatggtccaa aatatttttt 1440 agaaaagcat tcatctgtcc cgggatagaa gtagaggaag ctggtaggca ggcgctagac 1500 cctaaagaag gactgctgag ccagttctta agccagtggc tcttttgcct aaagcagcat 1560 tcctcaaact tctcactcga agcattaagt tacggtgaga tgctaacaca cgctttagac 1620 ttaagtcaaa atttactgtg aagccacagc aaaccatggc ttcacagatg aattagttgc 1680 tacacaaata agttcgatac ataagtacag taattgcttt taaaccttat aataagcagt 1740 aaattagaag ttaaaccatg tttttctttt acgaactgaa agaagagaat gcttttgata 1800 ctgagaatcg cacactgtgt ccaggcagat tgttcttgca taaccagacc cacaataaat 1860 atctacaact tttcttacat gtttataaaa taaatcttag aaaaaaaaaa aaaaaaaaaa 1920 aaaaagggcg gcc 1933 84 376 DNA Homo sapien 84 gcgtggtcgc agccgaggta ctccactcca aatttcccaa gaaattcaga agaattgtga 60 acaagttgct ggtttcacaa tactgcaagg acactgcaag gttattccaa gttcctcagc 120 aagtgtttac acattgggcc aaggacagat ttttcctgga gaaggatttt accactgcca 180 ccatcttgaa attcttcatc gttttggaac acagagccat agattttcat ttctgcactc 240 agctctgttc tgagaccggg gccatagggg ttcttggaga gacagggcag atggaagaag 300 tggaaggcat ctgccacact gtagagtgcc tttaagccac ccccattgcc tgagttgttt 360 tcctttttta caaatg 376 85 1325 DNA Homo sapien 85 ggccgcactt tttttttttt tttttttttc agagacggag agatttattt taaggaattg 60 tgtggctggc aagtccgaaa tccatagggc aggctggcag gctgaaaagt taagtgaggg 120 ttaatgccat agaccggagt cctgagtttg aattccacag ggcaacaggc tggaaactca 180 gatagggttt ctatgttgta gtctcaagga gaattccatc ttctttagga aacctcaatc 240 tttgttctta atgccttcaa ctgattggac agggcccacc cgtagtatgg tgggtaacct 300 gctttactga tttaagcgtt aatctcatct aaaaaaatac ctttaccacc atgtccagac 360 tagtgtttga ccaaacaatg agttggcata ctccacgcaa ggtgacgtgc aaaatgaacc 420 atcacagcac ttcttgtgtc ttcatgtgcc cacctggtac atgggggtac aactatctgg 480 cccaaagggg tggtcaatcc tgagtggata aataatagga atttagtcct atgatgtgtc 540 ttgatttttc ttttcttttc ttaccttcct atttttatta acccgggtct tctgcgccca 600 aagactcagc ctcattcagg accatattat gttcatactt ctgctgcgtc caaggagtgt 660 tgacgaaaaa gtggggcctt ggaggggtag aggccaaggg acagtttccc ctctgccctt 720 tgaagttcac gatcttccat gcaacaaaat tgttttctgt gaaaagcagg aaatgaataa 780 caacagcgta ggtgcgttgg ctatgtccgg tggcatttct tcagaatttt cattaatgac 840 acctgatttt ggaggcattg tatattttta aatacatcca gatgttgttt cagttgcttc 900 ctctttggtt ctttttgctt ttcgttgttg agcgtcactt aaattcgtgt catttcatgt 960 tggtacaggt actccacttc aaatttccca agaaattcag aagaattgtg aacaagttgc 1020 tggtttcaca atactgcaag acactgcaag ttattccaag ttcctcagca agtgtttaca 1080 cattgggcca aggacagatt tttcctggag aaggatttta ccactgccac catcttgaaa 1140 ttcttcatcg ttttggaaca cagagccata gattttcatt tctgcactca gctctgttct 1200 gagaccgggg ccataggggt tcttggagag acagggcaga tggaagaagt ggaaggcatc 1260 tgccacactg tagagtgcct ttaagccacc cccattgcct gagttgtttt ccttttttac 1320 aaatg 1325 86 744 DNA Homo sapien 86 gcgtggtcgc ggcgaggtac ttttaactta aaaaaatgaa catctttgta gagaattttc 60 tggggaacat ggtgttcaat gaacaagcac aagcattgga aatgctaaaa ttcagttttg 120 cctcaagatt ggaagtttat tttctgactc attcatgaaa gtcattcctt aattggaggc 180 ccaccattca attattcatc tattaattcc ttgatccttc atttatccat tctgcaaact 240 tttcttgagc accagcacgg gtggccattt gtggacttct cttcattcct atgtgttttc 300 ttatcaaagt gatccactct cgaaaggctc ctttccagtc tgtggttggg ttcaagtcat 360 gccagggcca gggggcccat ctcctcgttt agctctaggc aaaatccagg ggatctgcag 420 tggggagcgg gggcaggaag ctggagggaa ggcctgtgaa gggtagggat gtggaaagac 480 aaggtgacag aaggacccaa taggaccttt ctatatctct ggcttagcat tttctacatc 540 atattgtaat cgtcttattt gctagttttc ttccttactg tgagtgacta acagtcatct 600 ttatcccaag tgcctggtac ataataagtg atcaataaat gttgattgac taaatgtaaa 660 aaaaaaaaaa aaaaaagggc tgggggaatc agggccaagg cttgtccggg gtgaaattgt 720 ttccccccac aaaaaaaaaa aaac 744 87 1833 DNA Homo sapien 87 tgctccagga aagttctgtt actccaggga ctctctcttt tcctgataac atggccagca 60 agaaagtaat tacagtgttt ggagcaacag gggaagctgg tggcagactc cgccaagcac 120 ctgggtctga agcacgtggt gtacagcggc ctggagaacg tcaagcgact gacggatggc 180 aagctggagg tgccgcactt tgacagcaag ggcgaggtgg aggagtactt ctggtccatt 240 ggcatcccca tgaccagtgt ccgcgtggcg gcctactttg aaaactttct cgcggcgtgg 300 cggcccgtga aagcctctga tggagattac tacaccttgg ctgtaccgat gggagatgta 360 ccaatggatg gtatctctgt tgctgatatt ggagcagccg tctctagcat ttttaattct 420 ccagaggaat ttttaggcaa ggccgtgggg ctcagtgcag aagcactaac aatacagcaa 480 tatgctgatg ttttgtccaa ggctttgggg aaagaagtcc gagatgcaaa gattaccccg 540 gaagctttcg agaagctggg attccctgca gcaaaggaaa tagccaatat gtgtcgtttc 600 tatgaaatga agccagaccg agatgtcaat ctcacccacc aactaaatcc caaagtcaaa 660 agcttcagcc agtttatctc agagaaccag ggagccttca agggcatgta gaaaatcagc 720 tgttcagata ggcctctgca ccacacagcc tctttcctct ctgatccttt tcctctttac 780 ggcacaacat tcatgttgac agaacatgct ggaatgcaat tgtttgcaac accgaaggat 840 ttcctgcggt cgcctcttca gtaggaagca ctgcattggt gataggacac ggtaatttga 900 ttcacattta acttgctagt tagtgataag ggtggtacaa ctgtttggta aaatgagaag 960 cctcggaact tggagcttct ctcctaccac taatgggagg gcagattata ctgggatttc 1020 tcctgggtga gtaatttcaa gccctaatgc tgaaattccc ctaggcagct ccagttttct 1080 caactgcatt gcaaaattcc cagtgaactt ttaagtactt ttaacttaaa aaaatgaaca 1140 tctttgtaga gaattttctg gggaacatgg tgttcaatga acaagcacaa gcattggaaa 1200 tgctaaaatt cagttttgcc tcaagattgg aagtttattt tctgactcat tcatgaagtc 1260 atctattgag ccaccattca attattcatc tattaattcc ttgatccttc atttatccat 1320 tctgcaaact tttcttgagc accagcacgg gtggccattt gtggacttct cttcattcct 1380 atgtgttttc ttatcaaagt gatccactct cgaaaggctc ctttccagtc tgtggttggg 1440 ttcaagtcat gccagggcca gggggcccat ctcctcgttt agctctaggc aaaatccagg 1500 ggatctgcag tggggagcgg gggcaggaag ctggagggaa ggcctgtgaa gggtagggat 1560 gtggaaagac aaggtgacag aaggacccaa taggaccttt ctatatctct ggcttagcat 1620 tttctacatc atattgtaat cgtcttattt gctagttttc ttccttactg tgagtgacta 1680 acagtcatct ttatcccagt gcctggtaca taataagtga tcaataaatg ttgattgact 1740 aaatgtaaaa aaaaaaaaaa aaaaagggct gggggaatca gggccaaggc ttgtccgggg 1800 tgaaattgtt tccccccaca aaaaaaaaaa aac 1833 88 251 DNA Homo sapien 88 ttaaaaatgt aaaaaaatga aaaaaaaagt tttgagcatt atttgcatca ttgggataca 60 tatgtcactt cacaagatgt tcaatttgaa ggaaatacca ctcattctct atgtcctgtt 120 gtctgtagtg tgcttcagtt ttctcatatt gagttgacct aaatcctgga ttcatgacaa 180 gaaaggagta agtactacta ttcattgttc tatttgttta taatctgtat tataaaattg 240 cacataatta a 251 89 458 DNA Homo sapien misc_feature (327)..(327) a, c, g or t 89 ttgatattta tttagaaaac aagggaaagc ttttaattgt gtgcaatttt gtaagacaga 60 ttataaacaa atagaacaat gaatagtggg acttactcct ttcttgtcat gaatccagga 120 tttaggtcaa ctcaatatga aaaactgaag cacactacag acaacaggac atagagaatg 180 agtggtattt ccttcaaatt gaacatcttg tgaagtgaca tatgtatccc aatgatgcaa 240 ataatgctcc actctgtcgc tcaggctgga gtgcagtggc gcaattagaa ctcactgcag 300 ccctaaccct cttggcttaa acaatcnctc caccttagcc ctctgagtag ctagcactac 360 aggcacacgc caccacaccc agctaacttt tttgaatttt tggagacagg gttcacctta 420 ttttttctcg tgccnnnnnn nnnnnnnnnn nnnnnnnc 458 90 251 DNA Homo sapien 90 tggtcgcggc gaggtacaaa aacatggcag taggacaact ttgagctcaa cgcgcgcacc 60 tccccaggac ctctcacacc cacctgaccc atccaagggc cacaccaccc cgacagatac 120 tcccaccacc tttagaaaag agtcacccaa tctggagaaa ggtgtggagg ttacatcttt 180 agaaagaaat cattttaaat acatgaacat tagagaacac agtaaccgtg cttccaccca 240 gcacggggag g 251 91 2399 DNA Homo sapien 91 ggccgcatct ttttattttt tttttttttc ttacaaatgt gagttttatt tgcattctaa 60 cccaagcaca gatcccacat acagacttct cgtccgcact atggtacagt aacaagtgca 120 aaatatgctt tatttcaggt acaaaaacat ggcagtagga caactttgag ctcaacgccc 180 acctccccag gacctctcac acccacctga cccatccaag ggccacacca ccccgacaga 240 tactcccacc acctttagaa aagagtcacc caatctggag aaaggtgtgg aggttacatc 300 tttagaaaga aatcatttta aatacatgaa cattagagaa cacagtaacc gtgcttccac 360 ccagcacggg gaggctgcag agaggcaccc caaacagtcc ccttctcttc tgtggttaac 420 caagcaagcc ccgcaaagct tttcccagca gagcacaccc agccagcaat gaggcctcag 480 gacagagcca gcactgtgac aaaagaactt gtcccaccta tctgagagca tgagatctgc 540 aagtgggatc cggactggac accaggaagc tcaacctggc tcgggccatc agtagctgtg 600 ggaccctggc ccccatctaa cctcccagtt gacttcctga aaactgggct agtgggggcc 660 tccccattgc tttagggagg atcgagtgag aagctgacca aatgcgcaga acacaaagcc 720 tagcctgtta gccccagctg ctatcactac tgttactcac gaagaaagga actgcagtgg 780 ctgctgtctg cccctggagt gaagacacca ggggtgcaca gaggctggac aagccacagg 840 gggctggatg gccacagccg gacctcggac ccatctcccg tgggactcct tccatttgag 900 gctgtccatc ctccaatggc agatgcagaa ttctcaggcc caggataccc ttatggaggg 960 ccggggggcg gcccctcaaa accaccaagc tgaggccact gtgagcagtc ccctttgtag 1020 caggaagagc agctggacac atgggaagag gcttgcaggc tccagagaag ccaaaaggtc 1080 ctcagtcccc aaggtactag gtggaggtga gatcaggctg cccctcccag gacaagagtg 1140 tgagctggcc aggaggccac tgctgcccac cactgctcaa agtccttctc cacgcatcaa 1200 ccctgaggga cctggccagg ggatgcagac caaaggccca gcgggtcccc aggaacagga 1260 agcaggcggc aagaaggaaa gcaaagggct ctgcattccc accacgaggc ggggtggact 1320 ctgcaggagc cagctgaagc accagaacct tccaaggggg gctcgccagc cacacaggac 1380 acgagatgcg tgataggcag ggttaatgca gaaaccgctc atctgaatgc ttcccctgct 1440 tccaagcgca aaccaagtca ttttattctt ttaaaaaagc ccttactgtc tgaggctttc 1500 tttaaataat ccaacaggga tggaggtaat ggaggtctgg ctcagtagtc agcagacttt 1560 ttctgtaacg ggctagacgg taaatatttt gggctttcag agccaagagg caaaatcaat 1620 attatgttgg cgtaagagca aacaaatttc cacaattttt aaattgataa aatccaaaat 1680 acaataattg agtacatatt tttggtaaat acatgtctac taaaaataag aatttttttt 1740 tttgtgatgg gggagaaaac acttcattgg gttcaaagat aatattccct atcataaatc 1800 agtggcataa acagccagtg ggccaggtgg gcccaccgta tgctagctga caagggcagt 1860 cacacaccgg taagtgctga tacaggatga ggggtgcgga gctgaggatg ttgttctctt 1920 tgatgaaggc ctgaaaactt cccctggccc ctgctgccca cctcagggct cctcaggacg 1980 aagggcatga ggacaggttc ccactctggc ccttcgctgg gggacatggt ttggtttccc 2040 catcgccagg ctggccagct ggggcccaag cactgaccgt ccttccccac cttatcccat 2100 cagctgccct gcacaggagc agaaaaccca tgcctcagag ctacttccta aggacactgc 2160 ctctagaagg ccctaaagtg gcagagccgg ggatggcagg tgcagccctg gccactagca 2220 cagcagttgc cctcagatct gttagctgtg acccatagat tgggggaggg aggaaagcca 2280 ggaggagctt ttgcagaaag gtctggaagc taagtggggg tttcaggagc tctcagggtg 2340 cccctgggca ggtcccaagg aggcctgggg tgcctgacca gcacctcact ggccctcaa 2399 92 595 DNA Homo sapien 92 gtgatcgact cactatagca tgttatctag atgcatgctt cgagcggcgc ctagtgatgg 60 ataggtcgcg gcgaggtaca aatcattaag gcaaatctac aaaggaccag taaggcactg 120 gggcacagca gctgactgca ggaagtctat gtaacttccg gtagtaaaac agcctttaat 180 gcagacatag gtgtgaaaaa ttcagtgtta tgtttttttt tcagtgtcaa cctgcaccta 240 aagcacaaaa ggtcacttca agtcacttca atgtaataaa caattcccat tcatcacatt 300 accagtgaaa agagaaataa ttcactgggc tagaaggaat tagaagcagg aataaagaaa 360 atgccctttg gtttacactt actaaagaga atgtctttaa ctctccaagg aataccattc 420 cgctttgtga aattatacca attaattagg actcctctat attcccatta atgtcggatc 480 attacataac ttcaatagaa taaacacttt tttcccactt tgctataata atagctaggg 540 atacctcaac aatataataa tggtttaaat tatgaccatt tctctttggc cttgt 595 93 1457 DNA Homo sapien 93 cttatcctag agaataactc tgtatgaata aaattgctta attgagtctc ttactaaata 60 agtaactagt gccatgcttt tgtgagctct tggtatggcc catattactt tgtttttttt 120 ttttttattg ttgttttgtg atagtcttgc tctgtcgccc aggctgcagt gcagtggcac 180 aatctcagct cactgcaacc tctgcctcct gggttcaagc aattctcctg tctcagcctc 240 ctgggtagct gggactacag gtgcatgcca ccatgcctgg ctaacttttg tatttttagt 300 agagacaggg tttcaccacg ttggtcaggc tggtctcgaa ttcctaacct caggtgatcc 360 acctgccttg gcctcccaaa gtgctgagat tacaggcgtg agccaccgcg cctggcctgt 420 ttgttttttt aacatgattt ttctctaagc ttaaatacca caaggccaaa gagaaatggt 480 cataatttaa accattatta tattgttgag gtatccctag ctattattat agcaaagtgg 540 gaaaaaagtg tttattctat tgaagttatg taatgatccg acattaatgg gaatatagag 600 gagtcctaat taattggtat aatttcacaa agcggaatgg tattccttgg agagttaaag 660 acattctctt tagtaagtgt aaaccaaagg gcattttctt tattcctgct tctaattcct 720 tctagcccag tgaattattt ctcttttcac tggtaatgtg atgaatggga attgtttatt 780 acattgaagt gacttgaagt gaccttttgt gctttaggtg caggttgaca ctgaaaaaaa 840 aacaaaacac tgaatttttc acacctatgt ctgcattaaa ggctgtttta ctaccggaag 900 ttacatagac ttcctgcagt cagctgctgt gccccagtgc cttactggtc ctttgtagat 960 ttgccttaat gatttgtaca aatgactggg aggcggggat gctgcctgtg tcctggtgaa 1020 ccttaatgaa ggggccgtct taggcacagt gcaaaacaag catttgtcct gtactgttag 1080 agccaaaatt gtgatgagca atactgataa ttgtccagtt tatgtcatct ttcccagatt 1140 ttaaaatctg ttctagatat tcttagcttg aaccactttt gattgtgaaa tgtattaggt 1200 gttgtcccat tattactgta aaatgaagtt ttgaatcttc ttgttaataa actgtggatt 1260 tcccctctca atttcttaaa caacaacaaa aaaatgcttg aagattgtct ttgagtgtaa 1320 gatctgcctt ttcagaaagg gagtgttagt ttgtaatgtt aaaaaataaa gacctcattc 1380 aataaaagtt gaagtcatct tttaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 1440 aaaaaaaaaa actcggc 1457 94 936 DNA Homo sapien 94 tatcactata gcgatgtgct ctagatcatg ctcgagcggc gcagtgtgat ggattgctgg 60 ctgccggcga ggtacacaac gccttctaat ttgatcttca tgactgtaga cgggtgcccc 120 attccccctg aaacaacggt tgcgaggttt gcgcattact gcttcgcctg tgcatgacta 180 tcttgctgta actactagcg atgatcttgt atcgaattgt atctcagcca cttatcctct 240 cagtatagta caattaccat tgcatacttg tatacctcat ggagaaggga gttctctcca 300 gtcccaaccc atgaatgtgt tatcgattcg cgcattcgtt cgctcgcaac ctcagataaa 360 cactcttcat actttatcac taccttccat cttagtcaaa gctcaagaca aaaattaaac 420 aaaatgacac ctagccattc acctattaca accatcgacg tataagacac accattcgac 480 gtgaggaaat gacacacgta tttccatcaa cgagagtgct ggatgggagg gcaggacaca 540 gactggaagt cagcttcagc gtatacccac ttactcacaa gggctgacca tgatggccct 600 gctcttgcat gaggactcac atggacagcc agtggcactg atgcctgcag gactgcatgt 660 gccgacaaga tgatgcacat tttaatattc aaaatgtaaa caaagtatcc acaaatagtc 720 caaaaaagcc aaagaatggc tttacttaac aaatttttaa attgccctta aaagtgactt 780 tttggcataa tgcctttctt aaaaaaagaa ctctcacaaa aaaccatttt ttttaaccca 840 aaaacaatgc ctagatcact tcagaactga aatcctcaga tgaaacaggt gaacacttct 900 gtgactgcta cctctcagaa ggcttgggcg tatcat 936 95 480 DNA Homo sapien 95 tctcgagccg cgccagagtg atggatgcgg ccgccgggca ggtacttatt aagcagagca 60 ctttgtaaga ttcagaactg actcctgatt atcttaagcc attaaaagac tcaagttttg 120 catggacttt ttgtcctctt tggcccctga gtgtgcccca tctctgccca gcactaataa 180 cacgttggaa gagcaaagga tttcccacca gcgtgccaga tgatttatat aggcagggac 240 cttcattgaa aagaagggaa gggacactgt cttaaatgca catttaaggt tctttctgat 300 tattggcaat ctctatgaac caacacttaa tccatgggct aacagagaga tttttttttt 360 tttaatgtga agaggattaa agaataaaga aaaaacaaaa aagtctttat tctaaaataa 420 gaaatcagcc ccatctgtgg cacagttctc atgcagaata ttgcacccag tgtgaactag 480 96 1111 DNA Homo sapien 96 cgtccaatca gaggctctgt atttataaat aacccgtgtg ggattatgct ctccagtgaa 60 tataactgga gcctaaattc acaaccttaa gatctgacag ccagatgtgg aaggtctaca 120 aagagctctg ctaataagta atatgtttgc aaagtgctct gctaagtaag gtacttatta 180 agcagagcac tttgtaagat tcagaactga ctcctgatta tcttaagcca ttaaaagact 240 caagttttgc atggactttt tgtcctcttt ggcccctgag tgtgccccat ctctgcccag 300 cactaataac acgttggaag agcaaaggat ttcccaccag cgtgccagat gatttatata 360 ggcagggacc ttcattgaaa agaagggaag ggacactgtc ttaaatgcac atttaaggtt 420 ctttctgatt attggcaatc tctatgaacc aacacttaat ccatgggcta acagagagat 480 tttttttttt taatgtgaag aggattaaag aataaagaaa aaacaaaaaa gtcttatact 540 aaaataagaa atcagcccca tcttggcaca gttctcatgc agaatattgc acccagtgtg 600 aactaacgct agaagcttca aactgtataa atttaaatgt atttgcatat tataaaaata 660 aagataaaca tatacatatt ttacactagt tatggaacag caatgaacgt cagtcgatcc 720 ctctttcaca tttaacagaa ctgaaatctg agtgctctaa atactgccac ctgtactgta 780 actatggctt atatgtgcac ggaaaacaaa atccctgaga agccattcga cttttttttt 840 ttttttttct tttcttcaag tagcgcgctc cttggaggat cacagttctg aggttcaggt 900 tgtaaaacat ttgctccatg ttctcgtcca tgcttccccc caccaccccc tccccacctc 960 ttccccagtc atccaaaaag caccctgcaa gcacgcgttg tcactcaagt tcacagaaca 1020 cgctggggtg agtgcagagg gtctgccagg tgcaaaagat ggtccaggtg ttcagatgct 1080 ctcttttctc catggaaatt ccacagccac a 1111 97 395 DNA Homo sapien 97 gcgtggtcgc ggcgaggtac caccagctac ttcagagtga agaaagaaag tgtctttcgc 60 cactggttct taaggagtgg atctccggtc cacatctccc aatgctgctt agcccaggaa 120 atgaagacag ctgacaacac agaggaacat taacgaaaag aacaaacccc aaacttgaaa 180 tgcataactg ggactgctgg aatgggccaa ggcataccac ggcgggtcac tgtcaccagg 240 agggcgcctg tgttttagaa gggagtggcc aacaccgtct ggccaacctg gaagggagcc 300 aacgtgacag ctaagaacac tagacaagca tcctagcctt ctcacccatc gatctcagtg 360 tgatcttgcc acagagccac tggcaagcca ttcgg 395 98 3813 DNA Homo sapien 98 tttttttttt gcatacagaa ttattttatt taacttaaac catgtagtac tttactagaa 60 aaaagcagag taagagaaac taacgttgcc ttagcttcag ccattcaaaa tagacagttt 120 cttttttcca ttatgtaaag aatccagagt atatcgcaat aacaggaata aattcttaca 180 acagaatata caaaaacatt ttgaaatttt tttcatctac tgatttttta tataaacagg 240 attttttagg aataatttat acacagaaag tcattttatg taacaaattg gccatgttat 300 tacctttttt tttcttactt aaaaaaaatt tttttttaac aagaaaactc agaaaatgca 360 ttatttgcgg tgcatccatt ccatcccgcc ttctggtttg atttttttta tcccagacaa 420 agggataccc agaggtagac aaactctggc aaacctctca cctcaacctc actggcttag 480 aaagcagaca ggtgttttca ccgggcgtct cttccaccgg tggatgtgtg tgtgcaacgc 540 caaacatcca aatgaaaagt tgaaaacaaa acccaaatag tttccagatc tttctcctat 600 gtagcgcaaa aaccccaggt gtttcccatg atagagatat tgtggagttg gggagacatg 660 gccaacaatc cactggagtt agaggaagtg gagtcaactt taaaaccaat ttttgtgtat 720 gttatagttt ttattaaaaa ttcttttctg tattggaaat acgtatcttc ggggttctgc 780 cttaaataaa atagggtctc ttctgtgttc taacaaagca gtaatcaatc atgatacgag 840 gcatgtaagc aaatggcctg tgtgccccat agctgtcatc gtttatgtga tcactgtgta 900 tgctgtaatc atcatgaaaa ccattggctg tgcagtcaag tcttcccatg tccatggcac 960 tgtgctgaca atgacggcag ccagaccaat caagccagat gccgaacggt gccatgcact 1020 gctgggctcc aacacctcgg ctgtttccat ggccaatgag gttctttcca tctgtaaagt 1080 agctacactc caaagggaaa tgaccagtga aaaatgatcc ccgctcccaa ccagagggtt 1140 ctgggaagac ccagatactg aagatacaga actacttgtt aaatcatcat cattcctttg 1200 ttataaacta gggccaaaaa gcatgggggg aaaagagggt gaaccacgga tggggtcagg 1260 gagaaatcct tttttggcat attgtaaagc tagctagtaa acaggtgtcc taaaaaaaaa 1320 aaaaaaatgg atcacaaaca cacatttgca cacacagaga aaaaaaaagt gtctttaaat 1380 tattttcggc aattataaac tacaaacatt ttataaaatt attctgttct tacaaaaatg 1440 caatgaaaca tttaattagt tcttgtaaac cagatcttcg tcaactgact acccgtaatc 1500 tactggactt aagagcccta ttgaaaacgc taatgagtga ctagttaaaa caatgttgac 1560 cagaaagatg cggacacaca cacgtgggac ataaaaatga gtgatcgtta tgttctcgca 1620 gaaacaaaac gctaaagtca tgccccagaa ctgacaactg acgagtgcga tgtagtttgt 1680 gttcttgaac aattcgcctt aactccgaga tcagtttcca gagtaggatg ttaggtttct 1740 ttgttgaaac caaatgccca cggatgactg ctgagcctcg atgtggtctg atagcttcaa 1800 gaacaatcaa gttcaaaacc ttgcccacat tccttccaag ccctgcaccc tgctgctcgt 1860 aactcttctc tgtgccagga tccctgtgac aatggttctg tacccaccac ccggtcattc 1920 caccatcaag gagcactcac ttctccaaat gacgcaacca gtcatctaag atgaaggcca 1980 aaaatgaaac cctctgacct gtccaaggtc tgtatcttca gcatctctgg caacagaggt 2040 tcagtctaaa taacatcctc tcttgaagtt ctcatttgta ccaccagcta cttcagagtg 2100 aagaaagaaa gtgtctttcg ccactggttc ttaaggagtg gatctctggt ccacatctcc 2160 caatgctgct tagcccagga aatgaagaca gctgacaaca cagaggaaca ttaacgaaaa 2220 gaacaaaccc caaacttgaa atgcataact gggactgctg gaatgggcca aggcatacca 2280 cggcaggtca ctgtcaccag gagggcgcct gtgttttaga agggagtggc caacaccgtc 2340 tggccaccct ggaaggagcc aacgtgacag ctaagaacac tagacaagca tcctagcctt 2400 ctcacccatc gatctcagtg tgatcttgcc acagagccac tggcaagcca ttcggctgcc 2460 agcctgcaga ggtggactgc tgtgggaaaa gcttcagtgg aacaaactgg cctagaatct 2520 ggtgccagag aatagttggc tcataaatct tttatcccaa agcaccccaa tgtgcaccga 2580 gcatctcgcc atttggtagt tccacagtga ctgctcttct attttacgaa gccacttttc 2640 gtaccattga aatgtgactc cgcatcttaa gaaacaggcc aggagaggcc aggtcggcca 2700 cgaacacggt cttccatctt ccaaggagga ggctcgttcc aaaggtatgt caaacgtcat 2760 gacatcccac gaaggagacc tggggtggtc tgggtcttga tcaagttcaa cagtgtctcc 2820 agtacacacc agctcctgct gcctcaggga agggctgtgt gggagaacgt cttaatgctc 2880 acatcaattc catgatgtgc ctcagtggtt catatgactt caagcagtgt gagctgctgg 2940 cagaaggagg ttgcatggaa aatgccacaa ctcagcttaa gattatttgg aacacacaga 3000 gaaaaatcaa gaggcagaga aatcagcatg aagttaggct agaactgtgg atagatgatg 3060 ccttggtata gtcaaggtgg gtgggttggt ccagtaaaat gactgcacca tcacacaagc 3120 caagttttct cttttattga ggtgtttctg aagcatttgc tatgatgggc actacactgt 3180 tagtgttttc tacttaaaag ctacctacat aaaacaaaaa caaaatgaca tcagtaactc 3240 ggacagttta aacaaaaccc ttataaccag ctgaatgatc tgtagaaatc cagttgtgga 3300 aaccggtagg tatgtgcacg agaggagagg ccattattcc aaggggtcac ctacagtgtg 3360 gaagaacaaa accctgatcc aacagtattt ctcaatgacc ttaagatccc cggggtcctg 3420 ggagagatgg gtcgcgttcc agcaggaggc tcctgagcgc cttcacttag gctggaattg 3480 ccgaggagcc atccacgctt aggcaaagct gcccgccaca cttcccagcg aaatcatcag 3540 tgcctgtaag agcagctgct ggaagagggg agcgagccgt ctgtcctgtg agcagcagga 3600 ccagggagac ggaggtacag ccctggcggg gggggcgtga cgccacgagc ctcggcgccg 3660 gccactgggc tttccagccg gaaggtttgg tacatctctg tctaccccta gggaaggagg 3720 tgagggagaa gttgagaggg cagcctggag ggggagggga ctctgctcct gcgtgtgttc 3780 tatcagggac tggctgtgag gtccggagct ctg 3813 99 960 DNA Homo sapien misc_feature (716)..(716) a, c, g or t 99 atgctcgagc cggcgcatat gtgatggatc gcccgggcag gtaccttggg gactgaggac 60 cttttggctt ctctggagcc tgcaagcctc ttcccatgtg tccagctgct cttcctgcta 120 caaaggggac tgctcacagt ggcctcagct tggtggtttt gaggggccgc cccccggccc 180 tccataaggg tatcctgggc ctgagaattc tgcatctgcc attggaggat ggacagcctc 240 aaatggaagg agtcccacgg gagatgggtc cgaggtccgg ctgtggccat ccagccccct 300 gtggcttgtc cagcctctgt gcacccctgg tgtcttcact ccaggggcag acagcagcca 360 ctgcagttcc tttcttcgtg agtaacagta gtgatagcag ctggggctaa caggctaggc 420 tttgtgttct gcgcatttgg tcagcttctc actcgatcct ccctaaagca atggggaggc 480 ccccactagc ccagttttca ggaagtcaac tgggaggtta gatgggggcc agggtcccac 540 atgctgctga tggcccgagc caggttgagc ttcctggtgt ccagtccgga tccccacttg 600 cagatctcat gctctcagat aggtgggaca agttcttttg tcacagtgct ggcctctgtc 660 ctgaggcctc attgctggct gggtgtgctc atgcgtggga aaaagcttgg gccgtnaact 720 atggccatac ctgttccctg tgtggacatt gttctcccgc tcccatcccc atcccgccgc 780 acccaaccca ccccaacacc cacaccccac gcccccaaac gcccacaccc acaacaccac 840 acccccccac ccccaccccc ccacacccac cccaacaccc acaccctcgc ccccccccca 900 cctccaccca cccaccaacc cacaacacac cacacaccac ccaccaccag caccaccacc 960 100 2754 DNA Homo sapien 100 gccagaagca gcctcagctt ggcaaggtgt ggagatgact gctgttccct tcgcatttgg 60 ggaaaacagg ctccctcggt agctcgatga tcctcttttg atcttgtgtg acctcctgga 120 gagtggatga cgctggtggc cttagctttt ctagacagtg taaattgcac tgggcgatgt 180 ccccagagca gggcaaggtc tctagagcgg gtctcccaca tgactggctt cacacaggca 240 cttccgctcg ggttgcatgc tctgtgtcat cttaccggtc cagggttgca ggtaggaaat 300 gtttgtaccc tcttctgatt gccacctcct tcccatcgcc ccttagggac agggcttgag 360 ggccagtgag gcgctggtca ggcaccccag gcctccttgg gacctgccca ggggcaccct 420 gagagctcct gaaaccccca cttagcttcc agacctttct gcaaaagctc ctcctggctt 480 tcctccctcc cccaatctat gggtcacagc taacagatct gagggcaact gctgtgctag 540 tggccagggc tgcacctgcc atccccggct ctgccacttt agggccttct agaggcagtg 600 tccttaggaa gtagctctga ggcatgggtt ttctgctcct gtgcagggca gctgatggga 660 taaggtgggg aaggacggtc agtgcttggg ccccagctgg ccagcctggc gatggggaaa 720 ccaaaccatg tcccccagcg aagggccaga gtgggaacct gtcctcatgc ccttcgtcct 780 gaggagccct gaggtgggca gcaggggcca ggggaagttt tcaggccttc atcaaagaga 840 acaacatcct cagctccgca cccctcatcc tgtatcagca cttaccggtg tgtgactgcc 900 cttgtcagct agcatacggt gggcccacct ggcccactgg ctgtttatgc cactgattta 960 tgatagggaa tattatcttt gaacccaatg aagtgttttc tcccccatca caaaaaaaaa 1020 aattcttatt tttagtagac atgtatttac caaaaatatg tactcaatta ttgtattttg 1080 gattttatca atttaaaaat tgtggaaatt tgtttgctct tacgccaaca taatattgat 1140 tttgcctctt ggctctgaaa gcccaaaata tttaccgtct agcccgttac agaaaaagtc 1200 tgctgactac tgagccagac ctccattacc tccatccctg ttggattatt taaagaaagc 1260 ctcagacagt aagggctttt ttaaaagaat aaaatgactt ggtttgcgct tggaagcagg 1320 ggaagcattc agatgagcgg tttctgcatt aaccctgcct atcacgcatc tcgtgtcctg 1380 tgtggctggc gagcccccct tggaaggttc tggtgcttca gctggctcct gcagagtcca 1440 ccccgcctcg tggtgggaat gcagagccct ttgctttcct tcttgccgcc tgcttcctgt 1500 tcctggggac ccgctgggcc tttggtctgc atcccctggc caggtccctc agggttgatg 1560 cgtggagaag gactttgagc agtggtgggc agcagtggcc tcctggccag ctcacactct 1620 tgtcctggga ggggcagcct gatctcacct ccacctagta ccttggggac tgaggacctt 1680 ttggcttctc tggagcctgc aagcctcttc ccatgtgtcc agctgctctt cctgctacaa 1740 aggggactgc tcacagtggc ctcagcttgg tggttttgag gggccgcccc ccggccctcc 1800 ataagggtat cctgggcctg agaattctgc atctgccatt ggaggatgga cagcctcaaa 1860 tggaaggagt cccacgggag atgggtccga ggtccggctg tggccatcca gccccctgtg 1920 gcttgtccag cctctgtgca cccctggtgt cttcactcca ggggcagaca gcagccactg 1980 cagttccttt cttcgtgagt aacagtagtg atagcagctg gggctaacag gctaggcttt 2040 gtgttctgcg catttggtca gcttctcact cgatcctccc taaagcaatg gggaggcccc 2100 cactagccca gttttcagga agtcaactgg gaggttagat gggggccagg gtcccacagc 2160 tactgatggc ccgagccagg ttgagcttcc tggtgtccag tccggatccc acttgcagat 2220 ctcatgctct cagataggtg ggacaagttc ttttgtcaca gtgctggctc tgtcctgagg 2280 cctcattgct ggctgggtgt gctctgctgg gaaaagcttt gcggggcttg cttggttaac 2340 cacagaagag aaggggactg tttggggtgc ctctctgcag cctccccgtg ctgggtggaa 2400 gcacggttac tgtgttctct aatgttcatg tatttaaaat gatttctttc taaagatgta 2460 acctccacac ctttctccag attgggtgac tcttttctaa aggtggtggg agtatctgtc 2520 ggggtggtgt ggcccttgga tgggtcaggt gggtgtgaga ggtcctgggg aggtgggcgt 2580 tgagctcaaa gttgtcctac tgccatgttt ttgtacctga aataaagcat attttgcact 2640 tgttactgta ccatagtgcg gacgagaagt ctgtatgtgg gatctgtgct tgggttagaa 2700 tgcaaataaa actcacattt gtaagaaaaa aaaaaaaaat aaaaagatgc ggcc 2754 101 301 DNA Homo sapien 101 cagcggggga atgtatagac aatatggccc atggtgcact aatgctgcga gcggccgccg 60 agatgtgatg gatggtcgcg gccgaggtac atttaatcca tcttctccat ttcctccttc 120 aggagccagc tatgagattt cagtgcattt ctagcccagc ggatgttcat tctccactaa 180 acttcatctt ttactaagca aagggggatt attccatgag gcagccagga gcaaggggcc 240 atgatattca tgactttgtc tgctgggcat ttttcaaagt gtccttgaat tcactcagca 300 a 301 102 4318 DNA Homo sapien 102 gttgtatatg cttttttttt ttccaaataa acttgtcacc ctgcatgccc ttggcaaata 60 agtgaagcag aaataggaac acagtccaca ttcaagttga ggaacagtgt atctttaaga 120 gctgaccttt gggtgacctg gaaaggggga aagatggcta agcatggaga gaaacgaggc 180 aagagacaag ctatgataca acaccgcttc agcccctgcc ctcaatagca cacaacccac 240 atatcagctt tctctagaga aggaacctac tgtttagtgc tcctcacttt gcaatgtttg 300 tgctacgcca gaatttctcc agtttttttc attatcatcc ccctgagaaa aaaattacat 360 tgaatttaaa ttttccctaa taagagaaat taaatatgaa agaataggat tttgttgggt 420 aagattgagc tttggaaggt cacgaaccat tattctatct aaggtgtgtg ttttgttttg 480 tttttttttg tttttttttg tttttttttt tgcaatccct ctccccctga accaatttca 540 cattgggaat gcaggaccta gactgctgaa taaaaagcta cttcttctat aattgtcagg 600 ttctctccaa tttctcagct tcctcaaaga catggggtgg agttgggtgt gccatcactg 660 agagagctct ggaacttttg actcttagtg acatttttag atttaggggt tcatggcctt 720 ccacatgttg ccaccaactg gtgatctctg ccccttcatg ctgatcaaga aagtagaaac 780 tcctcgtcgc cttcaggttt gcagtcgcag aaacattgcc tgctgtggac tgtcagcaca 840 aaactgggac actggtgtca tttagactgt cagcagtgca catgattgta cgatagactc 900 caggcaacca tgtgcatctg tgcaagatga cctctgcccc aagagaaggg ttacggtcta 960 attaaatgtt taccaagatg gtaccagtgg gctctccccg tgtcctttgg tgttattgga 1020 gctggtgtat gacagactca aggaaatttt ttaaggaaaa tgaagaagaa atcaaccttt 1080 atggttctct ttcattggaa gaggagaata aggaaagaaa tggcaggtag agagggaggg 1140 ggaaaggaat agaaatggca tgtctttgat gctgtggctt gtgtggggac aatgggaaga 1200 gcacagcagg cacaacatat ctgtgttagt gccacgtggt atctgttaag tatggccaga 1260 gcctcacata taagtgaaga gagttaagac aattcttgct ctttgaacaa taatagtcta 1320 tagaatttct attggcaaac catcccagac aacctgacct atcaaacaaa agcaaataat 1380 ccctgtctca gaactgctgg tctaaaagct agaaggggca tgataatgga aattgctaga 1440 aaagagagaa tgctctactc tctttcctgt gcctacctac ccccatccta aaccctgtaa 1500 aacagaattt caaaatagat gtcaaatatg aagtaattca gacttccaaa gaaggaaaga 1560 gttctgccca gggcagtatg agcaaatcca cagggatgtt aagatttggt ccaactcaaa 1620 ggtttatggg cagtgagcct agagtctctt gagagtaaac ccttgcattt gggacaagga 1680 gaatatgtga agttcaggag tgctcacact agagcaagat ccagaaaaaa aaaaatccaa 1740 tggcatttta aactagattg cattatcact caatgctgtt actttgagca gacaaatcag 1800 ttgaatggga gggcaaatgg cagaaatgaa caaaagctat taggtgaaag catccccaat 1860 gtatcagttg tgagatgatt tttgtttaat gatgatcagg tttacattga agtggcttgg 1920 aagacgtatt tcagagggac tgggtttgta ctgcaaaact ctgaacacta gagcaggttc 1980 tactagcact tgggcagtaa ggtagcgggt gtgtattatg ctattgccat agttctcgtc 2040 tttgtggatt cacataccct ttcccatgag gagcttgcta ctaacagcct cctgtttctg 2100 ttgtttttat atgggagaag agaaagagct tggaatttca attgtctaaa caattggtat 2160 gatttacaag aaggcaaacc attcaggaga tgttcaacag tgtatcattc ttagcattca 2220 atacaatgtt tattataaaa tatacacctg agtttatgtt tttctgccag gctgaagggc 2280 aataatgtct tgctatgcaa acactctatt ttatgtgtga atttttttaa ctgtaatttt 2340 atgtgtgaat ttttttaact aaactctatc atcattttct atgttgacat cttttttttt 2400 ttttaatctg tttccaactc tgagtctgtg aactatctct tctgactgga tgctggccta 2460 aaatcctatt agtgcttaaa cagacctcaa aacactctga acctgtaggc caatacagag 2520 atgttgttct ttgatatatc ttgggtcctt gatggcttca acaaacaagg tcataatttg 2580 tttaaattca gtgttttctg tagatacctt cttctcagtt tcattaagaa gagtaaccat 2640 ctttggtttt ccaaagaatg gaaactccta ccctagactt tagacttaga gcgtctgcct 2700 ttcacgatga gtaagagatc cagaatgttt aggggatgtg cgtcagccca cctggtacag 2760 tggcaaagct gaatgcgaac ttgaggcctc ctgaggcctg accttctatg cccccagccc 2820 tccaccccaa gcaccttttg gtgtggctgg aaacacatga cattggatgt gatttttctc 2880 aagcccttca ctgtggaagg catgggagac tgcccagcat tgggcatgtg gctgttaacg 2940 tttccatttc aagtccctga ttcttactgg agaagttaag gagccactta atgttttcac 3000 agacctctga ttctgttgtg aatgtggcat tccagtgagt acaacctgct tgctataaag 3060 aaagcagcat attttgacaa ttttatttct tccttgggta cttacatttt tattacaaaa 3120 atggccgtta taaaaaaaga cagaagggct gggcagtggc ttgctcccta gaaactgaga 3180 ttccgaagca ggtgtttcct ctcccctaga ctcagaggta catttaatcc atcttctcca 3240 tttcctcctt caggaccagc tatgagattc agtgcatttc tagcccagcg gatgttcatt 3300 ctccactaaa cttcatcttt tactaagcaa agggggatta ttccatgagg cagccaggag 3360 caaggggcca tgatattcat gactttgtct gctgggcatt tttcaaagtg tccttgaatt 3420 cattcagcaa acaaagcttt ctggagaatc tctcaaaact taggccctgc tccatttggc 3480 caaaaatgat ggctgctcca aaactctgaa cttcttaaaa ctccatctgc tacattattt 3540 ctggagttta aacatgactt tttctgtctt tgagtataga tgtgtttgtt taattaacga 3600 agcacaagtc tgttaagcag aaggctccaa gctgtattct atacttggga atccttggtg 3660 ccatctttat tctaccaagt gccaatcacc atggctaaag tgggcgtata ttacagcctg 3720 tgtcctaagc ttagaagctt taatgtactt ttttaaatga aaagtattag agggggttga 3780 acattgtaac taaagcataa agttagacca attacatgca gagatgttta tttaatattg 3840 tgtgagctga gtccttctgt ataaattatt tgcacacttt tcttgcatga tgaactgatt 3900 ttttatagtt gtttgtacca gacggtggca tatttttgta aaaaactttt gacactgaat 3960 tgcaataaaa tgtttttcca acaaaaaaaa aaaaaaaaaa tgcggcagag gctgcggggc 4020 gacgcgcggg ccggcgcagc catggtgaag attagcttcc agcccgccgt ggctggcatc 4080 aagggcgaca aggctgacaa ggcgtcggcg tcggcccctg cgccggcctc ggccaccgag 4140 atcctgctga cgccggctag ggaggagcag cccccacaac atcgatccaa gagggggggc 4200 tcagtgggcg gcgtgtgcta cctgtcgatg ggcatggtcg tgctgctcat gggcctcgtg 4260 ttcgcctctg tctacatcta cagatacttc ttccttgcgc agctggcccg agatgcgg 4318 103 2288 DNA Homo sapien misc_feature (948)..(949) a, c, g or t 103 tgtgacggaa acattcacac ggaacagcta ggccatgata cgccagcttc cccgtctatg 60 ggataccaaa gttgccagca attaatttac attaccaaaa aggagaaacc attatttatg 120 ctatcaccaa agccataccc ttaaaagtaa aaacacatct ccacttgata ttagtaattt 180 gagaaaactt agcatatcta caactactgc ttaatccaca acttttcatt gattcaacat 240 tatcacttaa atgcagatgc aaaataaccc ttgcatggca aacatgttta ctctgtgcta 300 atgaaactat gaaacagttc ctgcaagttc acagacacag tcaatcaatg attgactaca 360 gaacagactg gtgagtgtta ccaaaaacaa aagacctgcc caggggacca ctaggggtgg 420 aggaagaaca cctgggtctc actcactggg cacttgatgc tttcattttt atctgtaagc 480 caggggacaa ttatattaat attgtatgaa tacactgcta ctgggaaaag cattcattca 540 acagatgccc agctacatac tctgtaccag gtagtgtgtt aagtgctgaa acagggaagg 600 acaaggcaca tcctacgggg gctcgcagtg tgggcaggtg ctgagctaac gcacacacac 660 aagggctggg tacctgccag atctgtatca ctccggagcc aacgacctgt ctctctgaat 720 gatctctggc atggtaaaag agttaactgc tatttcaaac aggctgaaca caaaactttt 780 tttgccttcg cttactgcac tgcttctcaa acttgactca cgctggcttc acggcctgcg 840 acgtactgca ctcacgaact tactcctgct gaacgccttg cgccgctaac tccactgcgc 900 tcactacgcc tgcttctccc tgctgctgca cacactctgc tctactcnnc cgctcacaat 960 ctctccacac aacataccgg agccagcccc ccccccctcc ccccgccccc ccccctgccg 1020 cccccccccc cccccccccc cccccccaac actataactc ctgcgctcag cgcctcacct 1080 gcccccgcac tccccccagc tccggcccac acaccatgcc ccgcagccca accctcgcca 1140 ctcccacact gcacctccgc gcctccaaac agcccccgcg accaacacac accgcgccca 1200 cacgccgact acccccggcc gcccagccca cccaccactc ccgacatgcc ccctccgccg 1260 ctccaccata gaacacctcc gccccggccc cgcgcccgac ggccccgaca ccgcgccccc 1320 gccgccgcca acgcccgcac gccaccaccg ccacccaccc ccacacacgc acccagccac 1380 cactacccgc caccatcccc accccaccac tcccacccgg cccacaacca ccgcccggcc 1440 acccaccaac acacgcccgc acgaccccca ccccgccccg ccccaccacc tcgccccgcc 1500 aacaaccgcc acccacaacg cgcccgcccc accgccccag ccacccatcc acacccaact 1560 accagccccc gccccccccc ccccgccacc gcaccccact ccaccaagac gaaaactccc 1620 gacaccgccc actaaacgca ttacagcaag ccgctgagac ccgaaaacaa ccccccgcaa 1680 gcagaggcac cgctaccatc aaacgcaaca accacacaac gcacggctat catccccccc 1740 ccaccgtgac cacaaacgca ccaccccgcc cgaccagcac gccacacccc cacggccatc 1800 acgcacagca ccacacccca cgcactcaca cgacgaaata cccccacgcc agccgcccaa 1860 ctcccacccc ctacggcaca aacccacacg gcggacccac acctaccaca cacacgcaac 1920 acaggacgca tcagaactac ctaaccacac gcacgaacac acaacagcac accacccccc 1980 aaccacggac gcacgagctg tcgacccact accaccacac acgatgaccc gacacagcgt 2040 gcgagcgcca tacccgcgga gcagcacagc caatgcacgg ccccacgacg gcgacacgcc 2100 gccatccttc agcctcgcgc cacccccgtc caccgaacca agaccaagac gcagaatcgc 2160 aggccgcacc acacccgcta cggtccgtag cgagacagca aacaacaaga cgactgcggc 2220 gccgccacca ccgccaagca actacgcaca accaccgacg cctcatcacc ccaccaccac 2280 aacactta 2288 104 592 DNA Homo sapien 104 ggatatcgac taactatagg ccatgttgac taatgctgct cgagccggcg ctgtgtgatg 60 gattggtcgc ggccgaggta cacatattca tgccactcgg ctctgaaaag aggttcaagg 120 tgggtcaagg tgggtcttgg ccagtggagg aaggaaggtg tccaggactt taggttaatc 180 aacagtgggg acagagagga atgatttccc ttgtgaaaac aacagggttc ctttctcata 240 ttcttgtggc cagaaactgg ggtgaacttc agttgtggtg taattgaaat gaaacagtga 300 gagccatttc tccatggaac tcctatgacc tccattttaa cttctgacaa agttaacttc 360 atttatacaa tctgtatttg aaaacagtaa tcacaaccaa aaaggtccta taaacctgta 420 atagatgtca aagggattca cattctgaac tttaatttta aggacccttt aaaaggccta 480 gacttggatt aaagtaaacg taatattcca agctaaaacg aggcaccata aaaaatcaac 540 tcaaaacatc caaacaatgg ctagatggac taatgtaggt tgttttgctt tt 592 105 2180 DNA Homo sapien 105 tttttttttt acatctgtac aagatttatt tcatttacca caagttttag agtgaaagta 60 tatgccctaa tacagaagga gtgattcaga acccaccaaa agatcaagag ccaaagtcag 120 ggcttgtatc ccaggtcaat aggagtttca tccgccattt gtttttctgg gattaaagag 180 atgatgtgca gaacgcccgg gctgagctca ctatggcttc tgacatacaa gcaccactag 240 gaacaagact tcatgcttca tccttgctct ggctgtgcta gtgagtggca aaagcctctg 300 ctcgtgcttg ccctccaaat ttttcacaag cattcctgtt actagccata gcttcccatg 360 acttcacatt tgagtaagtt atcctgaagt gtgtggctgt aatattgaca aatagaacta 420 atgagagtga actgccatct gtttaacaaa acgcactctt ctaagagaat acccagtctt 480 agtgcattta gtacatagtc acaacattga aatgacgtga gaatcaatac aaaatattta 540 ttttttttca aaccacagaa ttcttaaccc cagagccaca caataaagtt ctcagaattg 600 taagccatta acatttttct aaacaatgca gtccagagat gaagataatt tccaaccagc 660 agggatgcaa tatatagtag gttcccctat gaatgaagct caaattagca tttcctttaa 720 ttctcccaca gccactccat caacagaagc agaaacagta cacatattca tgccactcgg 780 ctctgaaaag aggttcaagg tgggtcaagg tgggtcttgg ccagtggagg aaggaaggtg 840 tccaggactt tagttaatca acagtgggga cagagaggaa tgatttccct tggaaaacaa 900 cagggttcct ttctcatatt cttgtggcca gaaactgggg tgaacttcag tggggtaatg 960 aaagaaacag gagagccatt tctccaggaa ctcctatgac ctccatttta acttctgaca 1020 aagttaactt catttataca atcgtattga aaacagtaat cacaaccaaa aaggtcctat 1080 aaacctgtaa tagatgtcaa agggattcac attctgaact ttaattttaa ggacccttta 1140 aaaggcctag acttggatta aagtaaacgt aatattccaa gctaaaagag gcaccataaa 1200 aaatcaactc aaaacatcca aacaatggct agatgactaa tgtaggttgt tttgcttttt 1260 agttgcaaag cttttcagta tctcagatta gtgtatgttc ataaaacaat gctcagttat 1320 tttaatagct gcttatgaaa caataacagt ttaactcaag ggcaatgctt cttgcataat 1380 aatcacaaaa ataattaact gctataaaac gggaaaaaaa gtagaagaaa ataaagccag 1440 cctcaataat aaaaaggcaa aatctggagg ggttactcgg cttaaaaaga gattaaccag 1500 gattatttaa atactataat acacagtgct cctgctcact tctaactgca gaaaccaatt 1560 ttgtttgcta gatcaccatt acctttgcta gtatgcgtac agaccaccac tcggaagtta 1620 tccttttgtg ctgaaaaacg ttcaaatccc ttgtttggtc agtacagaat attgcgaggt 1680 gatgctcatg caaactcttc ctgaggaatt tatgtgtgca aatctgcaac ccgacagcat 1740 ggcacgcagc cagggagtgg tagctgcaca gtgtgagcac tggagatgga tgtgcagtgt 1800 gcagtgttca cagccatgga catccattct tctgcaatct catctaccca caaattagct 1860 ttcactctag accccaaagg gagggtaatt gctgcaaatt tgttaaaggg acagaagaaa 1920 aagtagcttg tctacaaaat aatgcacaat gcatgcatct gggtttgtgt ttcttctcac 1980 taaccttgcc taagaaccat taggataaaa gtcacaacac caggttttgc tttctgcccc 2040 acaaaaaaac agtagttaat tcctgtcagg ttagggtaca ggtgtgacaa caaaaggtca 2100 caaaatgaca atgttactga agcttaaggc caacctttaa aacatgtacc gtctctcaaa 2160 acaattatcg atttactttt 2180 106 611 DNA Homo sapien 106 cgggcgtctg gcgcaggtac gttacggagc tatctgggag gaggaagccg tccacccaag 60 ctcacccgac tggttcaagg ttaacaatgg agagcctcac aaacacacgg aggcacttgc 120 gagaggcaga ggctggggcc acagagctgt gaggagagag tgaatctccg tgcatggcag 180 acatgttgtg agaggcagag gctggggccg cagagctgtg aggagacagt gaatctccgt 240 gcacggcaga cacacaaacc ccatcctcag ctgcagattc acaggagagc atgggggcaa 300 gtgggctctg cagttataca gcaggacagc gcacggcctt gggcaggcca caatttctta 360 aagggaatgg gaaaatgaga gcttacggaa agcaggataa agcgccctcc actcatgctg 420 aaaagcacga agacctgctt tccaggaatg acctgcctga ggccgggaca gtcagctacc 480 aatgcaagac acaagagcaa gaaggcccaa gtgcagagag cgcaagttaa ctcctccagc 540 tccaagacac agggtgagag caggctacgt gtgggcagag acggcatcta tctgcccatc 600 tctgggaaaa g 611 107 1845 DNA Homo sapien 107 cacgaccatc tcgcactacc ctgactacag ctggagcgcc cagaggcgag ccctggtgga 60 ggaagaggtg agctgagtgg ggcctatgct gggggaagct ggcccttccc acattccacg 120 ccctgagtgc ggagtgctgt tttccgccgg ggtgctttga gtctcgctct gtcaccaggc 180 tggagtgcag tggtgcaatc ccggctcact gcaacctccg cctcctgggt tcaagcgatt 240 cttctgcctc tgcctcccga gtagctgggg ttacaggcac acaccaccac gcccagctaa 300 tttttgtgtt tttggtaggg acggggtttc accgtgttgg ccaggatggt ctctatctct 360 tgacgtcatt tgtgatccac ccgcgtcagc ctcccaaagt gctgggatta caggcgtgag 420 caatgtaata aacagacttt attttttaga gcagttgaag gtaacaggaa gtggagctga 480 aaacacaggg tggccccatc catgccctct cacagcccct ccttcctctg agcccctcac 540 gtccttggct ctcctccgaa gcttcttttc ccagagatgg gcagatagat gccgtctctg 600 cccacacgta gcctgctctc accctgtgtc ttggagctgg aggagttaac ttgcgctctc 660 tgcacttggg ccttcttgct cttgtgtctt gcattggtag ctgactgtcc cggcctcagg 720 caggtcattc ctggaaagca ggtcttcgtg cttttcagca tgagtggagg gcgctttatc 780 ctgctttccg taagctctca ttttcccatt ccctttaaga aattgtggcc tgcccaaggc 840 cgtgcgctgt cctgctgtat aactgcagag cccacttgcc ccctgctctc ctgtgaatct 900 gcagctgagg atggggtttg tgtgtctgcc gtgcacggag attcactgtc tcctcacagc 960 tctgcggccc cagcctctgc ctctcacaac atgtctgcca tgcacggaga ttcactctct 1020 cctcacagct ctgtggcccc agcctctgcc tctcgcaagt gcctccgtgt gtttgtgagg 1080 ctctccattg ttaaccttga accagtcggg tgagcttggg tggacggctt cctcctccca 1140 gataccctca cgtaccctgg ggttctgggt gtcacagaag ctgctctggg tgcggccact 1200 ctggagcggg gcccttgtgc caggtgagac acccttctcc tcagcaagcg gacttggtgc 1260 gcagcaggcc aatacgtcgg tgccgacatg ccatgaagca cgggaggccg taggagattg 1320 agggaggtga atgactcagt cctcatcgta aggagcgcgc tgaggccgaa gatgagcagc 1380 ggagctggtg catggggccg actggcccca tccatgccct ctcacagccc ctccttcctc 1440 tgagcccctc acgtccttgg ctctcctccg aagcttcttt tcccagagat ggggcagata 1500 gatgccgtct ctgcccacac gtagcctgct ctcaccctgt gtcttggagc tggaggagtt 1560 aacttgcgct ctctgcactt gggccttctt gctcttgtgt cttgcattgg tagctgactg 1620 tcccggcctc aggcaggtca ttcctggaaa gcaggtcttc gtgcttttca gcatgagtgg 1680 agggcgcttt atcctgcttt ccgtaagctc tcattttccc attcccttta agaaattgtg 1740 gcctgcccaa ggccgtgcgc tgtcctgctg tgtaactgca gagcccactt gccccctgct 1800 ctcctgtgaa tctgcagctg aggatggggt ttgtgtgtct accgt 1845 108 160 DNA Homo sapien 108 ctgttacttc cttttgctgt cagagggttg ttgacaatgg caagggggga tgttagtgag 60 atccaggtgg tggtggcttc ttggtccact cagcttgcac acatgcaaga ggagggtctg 120 tggcccctca gccgtgctgg tggcctcctt cctcaagctt 160 109 4621 DNA Homo sapien 109 ctgagagaag cacgggggga ttgattggtg cttttagaga acacacctag atacaaatgt 60 gatacatttc tatactcaaa ttagaacaca tgataatgta gatttgttca ttcatcaaag 120 acaatcaccc attatagttg taattctcag tatttggctt ctcttgtgga tgatcagtat 180 tacttttctt tcataggtat tggatatgct ttttaggtct atcaaaaact aaagtctctg 240 aagtgacact ggtacaagca attcacttga atttctaaaa acagataaaa tataatggac 300 cggccgcggc cgccgggagt tttttatttg gaatattatt agatgatgcc ctatgataag 360 atgagacaaa tgatggggag ggaaggagga tggcccttct ctagaatcag caaacccaat 420 ggttctgtga aggtcagacc caagcttgga gcagctggtc tggatgcaga tccaggagct 480 gcagagtgtg gaacaggaaa ggctctgccc agggcccacg agctctagca ttcctgctgg 540 cagattagag atcttagtta aatttgacca agaaaggagc ttagctaaga ggtctttgtt 600 tccagaggac ccaagactac cagactcctg tgcagtctgc ctgtctgcag agcctccaat 660 cacggtttaa agtggtcttg gcctcccagc ccccactgct gcagccttca gagccagcct 720 ctggactcag cgccaggagc ctcctctcct gctgccctgg tacctgtcat cctagtgtca 780 cctatttgtt ttgcacagca ttctggagaa catgtgcctc acaaagtgat cctgtttttc 840 tcaccctcca aagctgaggt ggctaaggga ggcaggggtg agagagctca ctctctaaac 900 cacaggcagg gcaaggtgct tctaggccgt gtcccctccc tggggaatgg tcactactcc 960 tcagcatggc cacaggcccc tgtggttttg ggagtttgct gagtgactgg aatgggctga 1020 ccccagccgt ttccctgctg tggaagcagc aaggtagggg cactgctcgg tggtttgtca 1080 agctcagagg cagccacgga tggttaggaa caggaagcca cactgctaag gtgtgatgag 1140 ctagaaggga gacatcctgg acttcaagtg agacaagtgc agaggaggcc actccactta 1200 ggaccttcct cttagacctg catgagcacg tgtttcactt aagcacattg ggtccgaatt 1260 gtggcgcatg aacccagctg ttaaaccagg taccctggga ctgccctctg cctctcagag 1320 ccctacctgt cctggacttg aaggcgagca tcaggcaggc cttctcagcc catcttccac 1380 caggagtgca gagccagggt gctgagagga gcagggactg taactacagt aggaggcaac 1440 tttgctggtg tcattcctgc tcggattgac tttgtgctcc ctcccatcca cagctatggt 1500 agccagtatt tccccagcag ctctctagtg gggaagagtg gctagaacca ggccattctc 1560 agtcgaattt aggaagacca agactcatgt tcctgacagg acggtcattc cctcatggca 1620 tcactgactc agttctaatt cctcccctcc tgtttcattt tggtttgaac aacctgtgcc 1680 tgcagctgtt tcttccacct tcctggagct cacaattgga gcttcatgtt cagtcttgag 1740 ctcctaatgt ttccagacag ggcaggggat aggacagcca taatctatga aagctgtgaa 1800 acaaaccctg ggttatatag acctcagatg gtctcatctg aaggctttgc ccacttccca 1860 gtgagcagag ggtttgggga acaaagaggt agctgaagag tggtggtttt tccctgtatc 1920 ctgattttca gaaagggctt tagtctctga gctgtggcta gtagctggct ggctgaccag 1980 gggacggggg tctaataggg tgtctgacca taggacacct ctcgtgtttg gccttccctt 2040 tcttgtgtgt ttgtgtgtgt gtgtgcatgt acacacacaa atctgtatcc ccaggagtgc 2100 ctcctgcagt cactgggggc tcttccgtgg tgcaccatcc catgagagca gatcagaggg 2160 ctgtggtcag gacttcctcc cgagctgccc tccctccctg ggatgagttt cctctccacc 2220 tgctccaagg tgccttacga ggtgcagctc ttcacctggc cacatggcat ccatcaccgt 2280 gttgagaaat ggtgggacgt tggctggata ttgtgtgcta tgaatctgat ttgtccaaat 2340 ctggacctca gccaagccac ctgtggtgga accttgcaag tcaaggtcat gaacaaattt 2400 cttgtaacta ttggaaataa actaatgagg tagaactgtc atatccaaat ggaagaggtg 2460 gttggtactg ttacttcctt ttgctgtcag agggttgttg acaatggcaa ggggggatgt 2520 tagtgagatc caggtggtgg tggcttcttg gtccactcag cttgcacaca tgcaagagga 2580 gggtctgtgg cccctcagcc gtgctggtgg cctccttcct caagctttaa cttgtgccct 2640 ccctggcaac agggagtcat gggttaatgt cacctgtcat gcctctttct tcagggaaaa 2700 tattaaaagg ctcaaatcca agctgtgact tcccttagac agtgtaagcc tgtagggtgc 2760 agccccaagt ttatgtccaa aggctgcctc agaaccctgg agggagcagc gcccagctgg 2820 cagctcactc tccccttgca gttcactggc cttttcgcag ccaggctaag ataggcagtg 2880 caaggagctt cccactggcc agagcagctg ccttgtagaa tgtggggctg gcttttagaa 2940 gtttcacacg cttgcagcta agagtgcaga gctctctgtt ttacttcgtg aaacattagc 3000 agctctgagg ggcttggctt ttggtaaggg acttatagtc tgacttgcca caagcacctt 3060 gagctcctgg gttggttggt ggttggttgg ttgggttgtt ttaaatttga tttttctttt 3120 cctgaagttt gttagaagtc agacctatgc aaggaaaacc atggcccact tcagcagcca 3180 tccagtgggg gtgcttaatc ggtggtggta ggattcatgg aaacgttttt ttgaaatgaa 3240 agagaagatg atgtacttac attgtaaaat ggtttacaat aaagtttggc atcttattac 3300 agtttttttt aaaaagaaac catcacattt gtggttgttg gttgtgggtt ctctggagtt 3360 gaaacagctt ggcagggtca aaaaagattc ccctgtgaat tagaaggttc tccccaggga 3420 ccagagtgag aaggaacctt acgaagcctc atggcaggag tgggagccag caactgccca 3480 gtgaaaagcc aaacatgctc ttgccatgtc catctccact tcttcgctag tgagaattaa 3540 agcaagtccg tctctgagga ggacatcgtg ttggggaggt agagtataag cagtgagtag 3600 cccacatcct tgtccctgag gctgcggggc tggaaggagg tccctgggca gagccgcagc 3660 atcaggtgcc atctgcaggg gcacccctgg aactagtgga aggcccccac aaggcctggc 3720 ctgccctcag ctgcctcttg gcccatgtgc cacatcctgg gcattcctca tgtcagcact 3780 tgtctcagat caagcctggc agtcctctca ttggcctcct ggagccaggg tgtcaggagg 3840 gggattgggg tggggttcaa agtatgacag caatggagtg gcatttggga taaccaaatg 3900 tcagtgcctg gttgagttcc atctgcctgg agccttcgag gataaaaata atctccatca 3960 taaactgaaa aggacttaga tatgtgtgtt actgggaggg ctgcgaccta tgcacaccta 4020 ttccccatac ccaccccagg cgtaggctcc tggcctgtgc cctgggggat cttccccttg 4080 caaggagggg tgtgttagga gcttctagca aaggagagct aagtgacctt ccggggagcc 4140 cttgggcctg ttcttgtctc tgcagctcag tatctggagt gggcttcact ctcccccacc 4200 ctctttgagc aactgaaact gtcctgcagg ccagcccccc tgcggtggcc tcacctactc 4260 ggaggtgagt aggctcaggc ctgagcctga gcctgtttcc cacctctgtc tcatcagtgc 4320 tgtcaccatc gagcatggtt tcctccctgg tcctttccag accccttact cccccctctc 4380 tgaacttgca gttggaatag gatagaggac aaggacatca gcaaaaacat gagcaactcc 4440 ccaggctccc tttacctcac tttctccacc tgtgaacctg tggtagcccc tctctgagtt 4500 tgctgcaagg gcccagtgag cttgccataa tcagacgcag cagacacggg aagctcctgc 4560 tctgccacca tgcagggatg gaaaatctgt ccactggaat ccaggggaag ggatggaaga 4620 g 4621 110 303 DNA Homo sapien misc_feature (176)..(255) a, c, g or t 110 tccctgttat tgttccgtat attacctgta agcagatact gtattttatt ttagcctatt 60 tgacagaaca catcactcag aaaaagtgaa gtttcagagc aaacagtgaa gaaatcagtg 120 tgattgtaga caaaaagtcg gttcacagaa cggagcagcg gggggaggaa gggaannnnn 180 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 240 nnnnnnnnnn nnnnncccgg gggcagccgg ggctatgagg ggacgtgctg atgcgtgatg 300 atg 303 111 1848 DNA Homo sapien 111 tgtttttttg agacacgggt ctctggttaa ccccggctgg ggtgccatgg tgccatctcg 60 gctcactggc aacctttgcc tccccgattt aaggcggttt tttcccgcct ctagccctcc 120 ttgagtatgc ttgggactac agggcgccca cctctcacgc ccggcttatc tctctgtaat 180 tcttagtaga gacaggcttt tcacccacgg tggcccggct ggtctccaac tcctggcctc 240 cagtggtccg cccccctttg ccttcccaag tgctgggatt accggggtgg ggcccccgtg 300 cctggcccgt cctatcctcc cccccaccct tttttttttt tttttgacat ggagtctcac 360 gccatcaccc aggctggagt gcagtggcgc catcttggct cactgcaacc tccgcctccc 420 atgttcaagt gatcctcctg cctcagcctc ctgagtagct gggactacag gcgcccgcca 480 ccacgcccag ctattttttt gtatttttag tagagacggg gtttcgccat gttagccagg 540 atggtctcga tctcctgacc ttgtgatcca cccgccttgg tctcccaaag tgctgggatt 600 acaggcctga gccactgtgc ccagccttat cctcaatttt ctaagcataa ggatttaaga 660 gttagtggga aagcatgact acggtttaaa agaacctggt cagctgaagc agtcccactt 720 ggccattcca gtacacttcc tactctcgct tcatggagaa gaccgtctac tgacaagaga 780 atccatcccc tttgcacaca gtggtcacct gacagctcag aggtcaactt cttggttttg 840 aggaaaaatt caaaaggctg cacgtttaaa ggagttgttc catttcagtg ccccattagc 900 ctgtctttcc tcagaaattt accaatctct tgatgtgata agcaccaaac tatgaagctt 960 ttcccttcct ctccccgctg ctccgttctg tgaaccgact ttttgtctac aatcacactg 1020 atttcttcac tgtttgctct gaaacttcac tttttctgag tgatgtgttc tgtcaaatag 1080 gctaaaataa aatacagtat ctgcttacag gtaatatacg gaacaataac aagggactga 1140 aggtacaaaa cacacacgga cattatggtc atataaaata tatagaagta cctaacgtta 1200 acaatttttg taagaagttg cacattttgc tattttttta aagcatttcc ccacattttt 1260 tttcatctgt agatcctctg cagttaagat tgagcacccc cccgcaactt ttttttttga 1320 tacagagcct cgctctgtca ctcaaggctg gagtgccagt ggcatgatct tagctcactg 1380 caacctccgc ctcgcaggtt caagccattc tcctgcctca gcctcccgag tagctgggac 1440 tacaggcgtg cgccactgtg cccagctaat ttttttttgt atttttagta gagacaaggt 1500 ttcaccatgt tggccaggct ggtctcgaac tactgacctc gtgatccgcc tgcctcggcc 1560 tcccaaagtg ctgcgattac aggcgtgagc cactgcgccc ggccaagatt gagctccctc 1620 ttgcaatgtt tctcaaattc atcacgattg gaacataccg acggaattca ttttctgtct 1680 gaagcaatga gtgctataca tgaaagtttt cctcacatat aatattcatc aagtttattt 1740 acagtataag ctttccgatg ctaagggctg agatgtgatt aaaggctttg ccgtattcat 1800 cacattcagg aggctggggg ggggggatta atttaattaa ggatcctt 1848 112 333 DNA Homo sapien 112 ggccgaggtc tagaatgggt gaaggaatgt gttagtgtct ggagccatga aggccttgtg 60 ctgaccaagc tgctcacctc ggaggagctg gctctgtgtg gctccaggct gctggtcttg 120 ggctccttcc tgcttctctt ctgtggcctt ctctgctgtg tcactgctat gtgcttccac 180 cctgcgccgg gagtcccact ggtctagaac ccggctctga gggcactggc ctagttcccg 240 acttgtttct caggtgtgaa tcaacttctt gggccttggc tctgagttgg aaaaggtttt 300 agaaaaagtg aagagctgga atgtggggga aaa 333 113 2269 DNA Homo sapien misc_feature (2266)..(2266) a, c, g or t 113 gcgagcggct ggcggatccg acgcgcgaga ccgggagggg acgagggcgt tgcaatcgtt 60 cggggcgggg gctttccggg gagggggtgc tcaggtgcac cagcggcggc ggaccctcag 120 actctgccct cccctccctt taaccccctt ccagccggac gggaggcggg gcagggctga 180 gcatttgtga cacctacatt tccgtggctc ccttcttttc ccccgacccc tgtttatctc 240 ttcgccttcc agaagttctt ttccatcagg ccgtcgcacc ttgcgtggga aggagcaccc 300 cacttggaag caggaggcgg ggttcagatc ttggccctac ccctcctgtg ttaaagtccg 360 cgagcctcag tttccctcac agtatttttt gcctcgcctt acccggtttt gaggatctgt 420 acgagaaaga gaaaggaagt ggacatttgt tgaattcctg catggccaaa taccacgcag 480 actgcttcat ccgccacgtt taatccttat tacttggtgt tctcagaact cccatttcat 540 ggattcttaa gctcacagag tcagtgaata acagaaaggg attcagatct agccgtttag 600 ctgcacagtg gagttcttct ccagagtctt cccttgtctg ggctctggct ggaactattc 660 ctcagccaaa tcctcgcccc agaacagtgc ttcctgtttc tccagctgag aagtctccct 720 ttcagtttcc ttcttccagc acggagtaca ctgctctgcc tccacttaga ttacttcaga 780 aatgaaatgc agcaaatatt tatccagcag tgcagggagt tgaacttttg gagtcgggaa 840 ccttggattc ttgttctggc tctgccactt actgtgtggc cttgggaagt cctttgtctt 900 ctctgagctt tcttttctct ttgcgtaaaa gcggtgctct tgtcccattc tccctccctg 960 tcttccagca ggctctcccc ggaggctcag ccccctctgc tccccatggg caactgccag 1020 gcagggcaca acctgcacct gtgtctggcc caccacccac ctctggtctg tgccactttg 1080 atcctgctgc tccttggcct ctctggcctg ggccttggca gcttcctcct cacccacagg 1140 actggcctgc gcagccctga catcccccag gactgggtct cttttttgag atcttttggc 1200 cagctgaccc tgtgtcccag gaatgggaca gtcacaggga agtggcgagg gtctcacgtc 1260 gtgggcttgc tgaccacctt gaacttcgga gacggtccag acaggaacaa gacccggaca 1320 ttccaggcca cagtcctggg aagtcagatg ggattgaaag gatcttctgc aggacaactg 1380 gtccttatca cagccagggt gaccacagaa aggactgcag gaacctgcct atattttagt 1440 gctgttccag gaatcctacc ctccagccag ccacccatat cctgctcaga ggagggggct 1500 ggaaatgcca ccctgagccc tagaatgggt gaggaatgtg ttagtgtctg gagccatgaa 1560 ggccttgtgc tgaccaagct gctcacctcg gaggagctgg ctctgtgtgg ctccaggctg 1620 ctggtcttgg gctccttcct gcttctcttc tgtggccttc tctgctgtgt cactgctatg 1680 tgcttccacc cgcgccggga gtcccactgg tctagaaccc ggctctgagg gcactggcct 1740 agttcccgac ttgtttctca ggtgtgaatc aacttcttgg gccttggctc tgagttggaa 1800 aaggttttag aaaaagtgaa gagctggaat gtgggggaaa ataaaaagct tttttgccca 1860 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 1920 aaaaaaaaaa caagcaaaaa gacaagagaa gaaaacacaa gaagaaaaaa aaaccacaaa 1980 caaagacaaa agaaaagaaa agaagagacg aaaagagaga aacaagaaag aggagaggac 2040 aaagagcaag aacgaagaga gaagaaaaga gagcacacaa agagaagaga agaagcgaga 2100 ggaagcgaaa aagagagagg aaaaagagaa aagaagagaa gaccaaaccc gagaagaaga 2160 gagaggaaag gcgagcgagc aaagagcacg agaagagaag aaaggaagcg agggtgccaa 2220 gagaagcgga gagaacgaga gggagaaaag agggagagga agaagnagt 2269 114 550 DNA Homo sapien 114 agagatatat agcccgtctg ggctaacttg tgtcctctag atcatgcgtc gagcggtcgc 60 cagtgttatg tatcgctggt cgcggccgag gtacacacaa gaagccagaa gatatttttt 120 tttcagtgaa ctttctcctg gaagcaaagg agaagctatg ggagatccag gcatggtttt 180 ggcttctgga ggctgttttt tggttactgg ggtctcttca aagcaaaacg ggatcaggat 240 gaagaggggg aaaggcatgg gccataaata aataaggaaa tttgccccga ttctacaaat 300 gcatctgatg gaatgaggag ggtcaggctg tgagggattg ggggtagctc caggctgctg 360 ttagggacac acttgagctg gttcattccc tggagtgccc cgcaactgcg tctagggaga 420 ggcaggccca agcacatgtt cagtctaatt ccagctcaca ctggaaggct tcctataggt 480 ttggttgccc tgatcacagc cgagctgccc caccaggaat taaccctggt gggcaaaggg 540 tccatcttct 550 115 4441 DNA Homo sapien 115 agcgggggca tcgccgcccg cgcccctcta agtgccgggc cgcaagctcc accgcagccg 60 cctgcaagca gcggcgcctc ggccctcgac ctgcgcgcaa agcctgtgct ggagccgtcc 120 tcccgcggcg gggaccggga ccggggaccc aagccaatcg aaagctccaa ccatggccat 180 ggggctcttc cgcgtgtgtc tggtggtggt gacggccatc atcaaccacc cgctgctgtt 240 cccgcgggag aacgccacag tccccgagaa cgaggaggag atcatccgca agatgcaggc 300 gcaccaggag aagctgcagc tggagcagtt gcgcctggag gaggaggtgg ctcggctggc 360 ggccgaaaag gaggcactgg agcaggtggc ggaggagggc aggcagcaga acgagacacg 420 cgtggcctgg gacctctgga gcaccctctg catgatcctc ttcctgatga tcgaggtgtg 480 gcggcaggac caccaggagg ggccctcacc tgagtgcctg ggcggtgagg aggatgagct 540 gcctgggctg gggggcgccc ccttgcaggg cctcaccctg cccaacaagg ccacgcttgg 600 ccacttttat gagcgctgca tccggggggc cacggccgat gcagcccgta cccgggagtt 660 cctggaaggc ttcgtggatg acttgctgga agccctgagg agcctctgca accgggacac 720 cgacatggag gtggaggact tcattggcgt ggacagcatg tacgagaact ggcaggtgga 780 caggccactg ctgtgccacc ttttcgtgcc cttcacaccc cccgagccct accgcttcca 840 cccagagctc tggtgctccg gccgctcagt gcccctggat cgccagggct acggccagat 900 caaggtggtc cgcgccgatg gggacacatt gagctgcatc tgcggcaaga ccaagctcgg 960 ggaagacatg ctgtgtctcc tgcacggcag gaacagcatg gcgcctccct gcggcgacat 1020 ggagaacctg ctgtgtgcca cagattccct gtacctggac acgatgcagg tcatgaagtg 1080 gttccagacg gccctcacca gagcctggaa gggcatcgcc cacaagtacg agttcgacct 1140 ggcctttggc cagctggaca gcccggggtc cctgaagatc aagttccgtt cagggaagtt 1200 catgcccttc aacctgattc ctgtgatcca gtgtgatgac tcggacctgt actttgtctc 1260 ccaccttccc agggagccct ctgagggcac cccagcctcc agcacagact ggctcctgtc 1320 ctttgctgtc tatgagcgac acttcctcag gacgacacta aaggcactgc ccgagggcgc 1380 ctgccacctc agctgcctgc agatagcatc cttcctgctc tccaagcaga gccgcctgac 1440 cggtcccagc gggctcagca gctaccacct gaagacggcc ctactgcacc tcctactcct 1500 ccggcaggcc gccgactgga aggcggggca gctggacgct cgtctgcacg agttgctgtg 1560 cttcctggag aagagcttgc tccagaagaa gctccaccac ttcttcatcg gcaaccgcaa 1620 ggtgcctgag gccatgggac tccctgaggc cgtgctcagg gccgagcccc tcaacctctt 1680 ccggcccttc gtcctgcagc gaagccttta ccgtaagaca ctggactcct tctatgagat 1740 gctcaagaat gccccagcgc tcattagcga gtattcccta catgtcccct cagaccagcc 1800 taccccaaaa agctgacgtc ttttacagaa tgtgggatcc tcgagctaag atgagggcat 1860 ccctcacgtt cacacccctg gtggcatctg ccagccctgt tctggggaca aggcgggctt 1920 tcgtgggagc cgtgctcagc ctgccaggaa gccaagccct acagtgcaga ggaaacagaa 1980 tttcaacggg aagctggttt gcttcatacc attgggatct gctggtaaag ctgttatttg 2040 ggtttaggga ctgatccctt gcagtttact tctggatcac catgaatggc caagatggtg 2100 gcagaacacg ctgtggaccc tgagttagag acaatgcaaa tgttggattg ggtgtaattc 2160 tttttgaatc ccagatccag tctgtacttg aatatgagca gaggatctac aagaatgctg 2220 acagggaacc gtgttaagac ccagcacccc tattcccagg agcttctggc ctgaccatct 2280 gcagccaaag cactaacagg gacagatatg ggaatgtcca cctttgatcc gcatcctgca 2340 caatagtggt cccaccatgg ctgccacttt tttatactat ttggagaaaa gaccttgtat 2400 aaattcgagg cccgagtgac taacgtctct gtcacacgga aatgggtact tggtggcata 2460 gagaaacaca attagccact ttttcagcta cacttctcac tcagctgcac cctacacttc 2520 tcactcaggt gcaccccctt ctgctgtcct ttccccaacg tactgggtcc cgagcgtggt 2580 gggtatttgc cacactgggt gccagctcag cagcccccca cctctcttta ttctctccaa 2640 agctggtctt tctgactatc attgtggtag ggggaggaca gatgctaaag gtggaagctg 2700 acctggaaaa agagacacac ggggtgactg tggcaaagga cagctggaaa agaaactcta 2760 tcacttcttc attggcaacc acaaggcacc tgaggccatg gcactcccag aggctgtgcg 2820 cagagccaag cctctcaacc tcttctggcc ctgcgtcctg cagcgaagtc tctgctgtaa 2880 gacagtagac tccttcgatg aggtgctcaa aaatgctacc cggggtggtg gtgtctggct 2940 tgcagtctgg cccagttcag agaaagttgc agagatcagg ggccaaggat gtcatagccc 3000 caggttgtcc tcagggtccc aatcctaggg cagggtgtgc atggaagcaa gaactatgga 3060 aacctagctc cagtctgcag gctctgagcc cctagttcct cactccagcg gggctccctc 3120 actgcacaga acccacccct tctgtgtggg cactgctgac cacacagatg acccagaccc 3180 aaagagcctg gcagaagctc tgtggttgga gctgggctcc gtctccaggt ctggttcagg 3240 gggatcagga aggctctttt ccacctgtgg cttcactggc cctttgagat ttcctatctc 3300 accgttactt cagttaccct tgcagggggc cagggagtca agaatatacc gtgttcctcc 3360 agggtttaag ccggccatgc cttcccgaga gcataaccaa cttgacaggg gtgcccagtt 3420 accccacaaa ctgaaggaag gagatccttc ccccatcccc aggagtgctc tcaaccagcc 3480 tcagaaagct tgagaagatg gaccctttgc ccaccagggt taattcctgg tggggcagct 3540 cggctgtgat cagggcaacc aaacctatag gaagccttcc agtgtgagct ggaattagac 3600 tgaacatgtg cttgggcctg cctctcccta gacgcagttg cggggcactc cagggaatga 3660 accagctcaa gtgtgtccct aacagcagcc tggagctacc cccaatccct cacagcctga 3720 ccctcctcat tccatcagat gcatttgtag aatcggggca aatttcctta tttatttatg 3780 gcccatgcct ttccccctct tcatcctgat cccgttttgc tttgaagaga ccccagtaac 3840 caaaaaacag cctccagaag ccaaaaccat gcctggatct cccatagctt ctcctttgct 3900 tccaggagaa agttcactga aaaaaaaata tcttctggct tcttgtgtgt acagagacaa 3960 cagaactcgg tggggaaacg ggaatctttt ctgcaccaaa gctgcttcta aagcagaaag 4020 cagtggggct cttggtgttt catgctgcct tatttatatt aaaggaagaa ttaaatcttg 4080 caaggagtaa aaatggtcac tgtttggttt ttaaacttca ggaaatctgt gaggctccca 4140 gggcagagtt ggggacaggg gggtggattt cctattgaca aagcagaagc tttcactccc 4200 tttttattct tacactttca ggagacttta aaaaataaca aaacagaaca tttctaccct 4260 gtctttgagg caacttgtgt gctgcccgca gggctccaga aagggccttt gaaagctggc 4320 cgtagggtgg attccagcct aagaccttat ttcacagagc taatgtcagc gagagatata 4380 ggagctggaa ctaacaggag cgtttggttt tagagaaaga ggaggtgtct tggataactc 4440 t 4441 116 120 DNA Homo sapien 116 acttacaaac tgtggtcatg ttaagataca gaacatcagc caagaaccag aaccaactcc 60 ttaacataac atagagtggg ccctgcccac cccccaatac aatacattta agataagctt 120 117 1977 DNA Homo sapien 117 ttcacccggc cctcgcctgt caccttcaca gagaaggggc tgcctgcagg aagaaagcac 60 ggcccacgcc cctccagtca catactgcct gtgggccctg gtgtagtgag gggggctgcc 120 gaggcactgc tgcactcacc aggcacgtgc tggtcggcaa acttgatgtt gatgatgtag 180 ttgcctggct ctgtggggca gtaggtcacc tggcgggaca ggtgcctggc tgctacaaac 240 catgcaatga gccatgcccc gccctggaca cccccgccca gcatctgggc ctccacgctt 300 gggaccgtgg gagcggccaa cagagctatg tctggagaca tatgataaac cacctcagcc 360 cccaccaagc cgccgcaccc gtagaccaga ccccaaggac cctggccacc atgggccaga 420 gagcattacc ttcatctctg gctctgctga gccggccctt gagtccccca cctgctgcct 480 gctctggcga ccctgggtgt gggagtggtg ccgggctgcc ttctgcttcc gcccgctgcc 540 gggattgcct ccagcgctgt ggaggcctgt gtgcggggat gcagcccctg cctgtctact 600 gaggactccc actgagggga ctgctgaagc caactggtgc caaggagcac aatggagtgc 660 cccccagccc tgatcgtgca ccccccagac cggcgggatg gccaggcggg ctgcaagtca 720 accatgggca gcagcttcag ctaccccgat gttaagctca aaggcatccc tgtgtatccc 780 tacccgagag gccacctccc cagcccctga tgcggactcc tgctgcaagg agccactggc 840 cgatccccca cccatgcgag cacagcctgc ccagcacctt tgccagtagt cctcgtggct 900 ccgaggagta ctattctttc catgagtcgg acctggacct gccggagatg ggcagtggct 960 ccatgtcgag ccgagaaatt gatgtgctca tcttcaagaa gctgacagag gctgttcagc 1020 gtacaccaga tcgatgagct ggccaagtgc acatcagaca ctgtgttcct ggagaagacc 1080 agtaagatct cggaccttat cagcagcatc acgcaggact accacctgga tgagcaggat 1140 gctgagggcc gcctggtacg cggcatcatt cgcattagta cccgaaagag ccgtgctcgc 1200 ccacagacct cggagggtcg ttcaactcgg gctgctgccc caaccgctgc tgcccctgac 1260 agtggccatg agaccatggt gggctcaggt ctcagccagg atgagctgac agtgcagatc 1320 tcccaggaga cgactgcaga tgccatcgcc cggaagctga ggccttatgg agctccaggg 1380 tacccagcaa gccatgactc atccttccag ggcaccgaca cagactcgtc gggggcaccc 1440 ttgctccagg tgtactgcta acccctgcca ggcccagctg ccacaccctt tctgggagaa 1500 gcatggccta cagaatgaag agggggacca ggaacccctg tgggagaggc ttagacctga 1560 agcagtgccc actctggctc ctcctgcctt ggctgactgg gttcctggac catgtgcatt 1620 tcactgggcc atgggatcta catctccttg catccccagc tggtctgatc cctgccaggg 1680 ccccttcctt cctgctcatg gtcttcaggt ggcctgatca tggaaagtaa ggagttaggc 1740 attaccttct gggagtgaac cctgactcca tccccctatt gccaccctaa ccaatcatgc 1800 aaacttctcc ctccctgggg taattcaaca gttaaaagaa gcttatctta aatgtattgt 1860 attggggggt gggcagggcc cactctatgt tatgttaagg agttggttct ggttcttggc 1920 tgatgttctg tatcttaaca tgaccacagt ttgtaagtac ctcgctcgcg accacgc 1977 118 182 DNA Homo sapien 118 catgttctct aatgcatgct ccgacggcgc atgtgatgga tcgcggcgag tgaaaagcaa 60 gagccagaat taagaggttg ggtcagtctg gcagtgagtt catgcattta gaggtgttct 120 tcaagatgac taatgttcaa aaattgagac atctgttgcg gttctttttt tttttttttc 180 cc 182 119 875 DNA Homo sapien 119 ggtcgcggcc gaggtaccac attggtccac ttgacactaa ccaatcgatc attttttttt 60 aatcaagaaa gctagattct atcagataaa atcactgctt ctaaagagtt taaatctagt 120 tagaaaaagt tatagaaatg tttgcaaaga taagtaacag atagagtcag tagaggataa 180 gatcaaaaac aaaaccaagc aaaagatgag ttcaggggag tttgccatca agtggcaaaa 240 ctgacttact tagggaagaa agttataaaa caggaaaata tgagatgaac cttgagtgat 300 gtggaagatt tagataaatg gaaaggaagg agaaaatgga gttctttagg tggttgtaat 360 tggaggagga aatgaataca cacatcttgt tgacttaaac ccagacattc agcagctctc 420 tatacatatc tggaaaagac tgcacagtca cctcctgtct ctcaccccag gtattactta 480 gaattattat catatttccc ttcctttaaa gtaagtaagg gtgatggtga caatatggag 540 aactatgatt tttccattaa cctaataata attgtattta ttgagttctg ttaagcattt 600 tacatattaa ctcacttaag cctttcaaca gcctgggcaa aataggtatt attatccccc 660 attttacagg caaagaaaac tgaggtttaa ggtaactgtg ccgaaagtgc catataacag 720 ggctcacatt cagtatctgc agttgcaagc tcatgatcta tagtgccaag ttgcatatgg 780 tagtccatgt cacattatta cccttttata tccctggaat tttcatgggc aaccattagt 840 attcatttta atatcactaa acttccagcc ctgat 875 120 987 DNA Homo sapien 120 ggtcgcggcc gaggtaccac attggtccac ttgacactaa ccaatcgatc attttttttt 60 aatcaagaaa gctagattct atcagataaa atcactgctt ctaaagagtt taaatctagt 120 tagaaaaagt tatagaaatg tttgcaaaga taagtaacag atagagtcag tagaggataa 180 gatcaaaaac aaaaccaagc aaaagatgag ttcaggggag tttgccatca agtggcaaaa 240 ctgacttact tagggaagaa agttataaaa caggaaaata tgagatgaac cttgagtgat 300 gtggaagatt tagataaatg gaaaggaagg agaaaatgga gttctttagg tggttgtaat 360 tggaggagga aatgaataca cacatcttgt tgacttaaac ccagacattc agcagctctc 420 tatacatatc tggaaaagac tgcacagtca cctcctgtct ctcaccccag gtattactta 480 gaattattat catatttccc ttcctttaaa gtaagtaagg gtgatggtga caatatggag 540 aactatgatt tttccattaa cctaataata attgtattta ttgagttctg ttaagcattt 600 tacatattaa ctcacttaag cctttcaaca gcctgggcaa aataggtatt attatccccc 660 attttacagg caaagaaaac tgaggtttaa ggtaactgtg ccgaaagtgc catataacag 720 ggctcacatt cagtatctgc agttgcaagc tcatgatcta tagtgccaag ttgcatatgg 780 tagtccatgt cacattatta ccccttttta tatccctgga atttttccat gggcaaccat 840 tagctatttc atttaataat cacctaaaac ttttcagtct tctgattaaa attacgctgg 900 agtgatagaa tgtattttca tgatagaaat tgggaaaaaa aatggggaat gaagtttatc 960 agcatttcag acttgttttt ttttttt 987 121 295 DNA Homo sapien 121 cgtggtcgcg gcgaggtaca taaagctatg attttgcatg ggaactcatt taaattaaag 60 ttaccaaggg aattccatat gtaaactttt cctggaacta tgaacttctg agacttcaga 120 aagattttga ctgtgtaggt tattctgtgt tgcgctatgg ggtccgcctt tgtgttgctg 180 agctggagag cgtgcctctg ctgccgcgct gtgtcagtag tggggattgc acttttgttt 240 ccagctacag gccaaatttg agcaccttga gagacttcac caagaagaga gaatg 295 122 3210 DNA Homo sapien misc_feature (954)..(1013) a, c, g or t 122 tagtgtaaat tctactatga tgagtatttt tatatgtaaa gctttctctg aatttaggat 60 ttttttaagc ctagatctca ggacattgaa agactatgga aaaatagaat acagttttaa 120 cattcttgac atagttgaca attgacactt gctttccagt gatgtttact agtacagttt 180 tcaataactg tttactgcat atattttatt tggaaaatag tgttgttgtt tttttccttt 240 ctggtaattt ctttctatac tttgcatctc ttatttttat tgagcatgga cttgagagac 300 tttaagaagt tttgtaggga aaatacacac cgagaaaata aaaactctag gaaaagttca 360 caatgtttta aaaatagttt tgtacataaa gctatgattt ttgcatggga actcatttaa 420 attaaagtta ccaagggaat tccatatgta aacttttcct tgaactatga acttctgaga 480 cttcagaaag atttgactgt gtaggttatt ctgtgttgcg ctatggggtc cgcctttgtg 540 ttgctgagct ggagagcgtg cctctgctgc cgcgctgtgt cagtagtggg gattgcactt 600 ttgtttccag ctacaggcca aatttgagca ccttaagaga cttcaccaag aagagagaat 660 gaagcttgaa gaaaggagag acttttggaa gaagaaataa ttgctttctc taaaaagaaa 720 gctacctccg agatatttca cagccagtcc tttctggcaa caggcagcaa cctcaggaag 780 gacaaggacc gtaagaggta agaggcccag ccaccctcag gttgctgccc tgcccacact 840 tgtcacattg ccctgtcgga tcttcctagc gcttcttact tctgcttcct tatgctttgt 900 cttccttctc caactaaatg tcagctcctg gagaggagag accttgtccc tctnnnnnnn 960 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnntttgcca 1020 aaatgaatga atgaacaaaa taaaaataca tcacagtgtg aaaaggatca gttagctggg 1080 ggaaaatggc tgctcttatt gaatagccca gctgtggccc tagtacacag ctaatggctg 1140 ctgacctacc atgagttatt ttgaatttca tgtctaaata aagctgtgcc ctttgttggg 1200 gaattataga cataagatag tattttattg aattaattct taggttcagt tttttagaac 1260 aaattctact gatactgatt ttgtgagaat ttttatttta ataagggaac caggctgtcg 1320 attcgaactc ctgtgcattg atgtcagagc ttgtgaaacc aatggtggac gtaaagacgc 1380 agagaaaggt agagagggcc acagtgcaag ggggcagcca tgagtagcat gtggatgata 1440 atcgcaaggc gtgtaggttt ggggtatgtg ttaaaatcag ttacccaagt tttagaaaat 1500 aagtttattt ttcctttttg ataatttcct tctgtacttt gtgtcccttg ttttatttct 1560 cccacttaag tatccctgtc ggtttaacta tttggctctt gaggaaattc atcatgcctt 1620 gttctattca gaatgctcat ttgggggact ctgcctcagt ttactctagc tacctctgtg 1680 ctagcagcgt tgcatgctcc catgttcccc acagagcaac acatctggtt taatgctctc 1740 actgcatcta tttcagaccc attttcagaa tattgcaact caactttaaa ataggaaaac 1800 ataaccttgg cccattggtg gctttcaatt tttaaatatg gagaagtaaa ccacaggact 1860 ttggcagatt ttattggctt atatatttta caggtatttt tgtttgtttg ttatgttttt 1920 ttggaaaaga ggaaggaatt ctcatgtatg atctttcnnn nnnnnnnnnn nnnnnnnnnn 1980 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 2040 nnnnnnnnnn nnnnttattt ttgaaagaat aaatagtata aaagctgtat tttattcaag 2100 cattgaattt agaaagataa actataaatt tattactgct tttcaacatg ctttggattt 2160 taaagctaat ggatctttta ttaatacctt ttttcctttc atcttaaccc agtgttacta 2220 aaattagatt tcccattttt tcccctatat gaaagataat ttacatttac cttgtaaaaa 2280 ttatcaccct gctccacttg agaaccctgc tgttgtttgc aaaatcagga ccaagcccat 2340 attttttgag agctctctag aagaatttat cttcaagaaa atatggtttg gtgtttttgg 2400 ttttttcttt tctttttcaa agtcccatgg ccagatatcc tataatatac tagatgcatg 2460 tttgctaatt tttacttgaa ttttttttaa attgtaccaa tcaaaaggtt ctttttcttt 2520 ccagctccaa ttttttgtaa aacagaagtt ccagagcaca gaaggtcatc atcacaagca 2580 aactttatta aaaaaaaact agaagtgtgc tttgattttg ctgttatttg ttttatcact 2640 tctatatttg gtgaacagcc acagttactg atatttatgg aaaagtactt tcaagtacaa 2700 ggtcaataca taagccagag tgaatgatac tacaagttga gcatctctaa ttcaaaaatc 2760 tgaaatccag aagcttcaaa atctgaatct ttttgagcac tgacttgacc ccacaagtgg 2820 aaaattcccc acccgacacc tttgctttct gatggttcag tttaaacaga ttttgtttct 2880 tgcacaaaat ttttgtataa attactttca ggctatatgt ataaggtgga tgtgaaacat 2940 gaattatgta attagagtcg ggtcccgtag tgtatatgca gatattccaa acctgaaatc 3000 caaaacactt ctggtcccta agcattttgc actaagggat actcagcttg tacctatata 3060 ttcctatata ttcactgttg ttagaaatgt ttaagttgct gttctgtgat gaatctaaat 3120 cttttctctt gctaccaagc tattgtcact gcagtgcatt ataccaaaga gcgaagtcag 3180 tgccactgaa aatacagaac cattatatcg 3210 123 662 DNA Homo sapien 123 gcgtggtcgc ggcgaggtac ctgcatctaa aatagaattt atttttcttg agacacgtct 60 ttcaggcaga ggaaaggtaa tgggcacaca aaccttgatc atcttcttat aaaacaaggc 120 agcatccaca tttcaatact gtagcatatg aaataatttc tcaattccta ctctgtcata 180 gcttaaatga cttactgatt aaaatatgag taacaataat tctggagctg aaagacattc 240 tcaagccaaa aggtaacatt aaacaatgtt ttactttaaa tttaatgtca tgtagggtca 300 ctaaaaacaa aatgtaaggg ataaatgtaa gtgcataaaa cagagataat accaatttcc 360 acaaatacaa cttttattat ccaaaatcat cttggaagga ctttttctaa tatgcccatt 420 ttctaaataa gattaaccat ttgatgggaa tatttccaat tgtatcacct ccttccttga 480 ctttttcttc atcaacttag ggcctgggtt gtaggcactg tggctctttg ggatagttaa 540 atgggtgcaa tttggctgag accgcccctg tcttaaatgg cccaggctac agggcttgcc 600 aaatggcttg tggtttgcaa cctcttcctt tgatatccat tgaagaacac atgtcctacc 660 ct 662 124 1845 DNA Homo sapien 124 tgtcagattg atggcctgtg ctgttgagta gttccgtctg attgacgtgg cgattcggat 60 gtggtcgggt gtggtgagtg gctgggtggg ctttcggtgg gtggtgtgtg tgcggccggt 120 ggtttgtgtg tgcgtgtgtc gcggcggtgt gggctgtggg tcggacggag ggcctggtgg 180 cgttgttaag aggctcgggt gtcggcgggg gtgtgttctg ttgggggctc gtcgtgtccg 240 ttcggtggtc cggcgtggtt gtgtggatat cgtggtgtcg cgtggttgcg tggctgcgct 300 ggtgcgggcg tggcttatgt tgtgttttaa tgcgttgctc gtggggtcgg tggggtcgtg 360 gcggtgtggt ggtgtgtatg tgtggtgttt gttcgcatgg ggcgtgttgt atgtgttggt 420 ggccgcggta ggagtccggc catctcctga tttattcttt tacagttttc tatgttttga 480 attgatatca attcttagaa taaaatgcag tacctgcatc taaaatagaa tttatttttc 540 ttgagacacg tctttcaggc agaggaaagg taatgggcac acaaaccttg atcatcttct 600 tataaaacaa ggcagcatcc acatttcaat actgtagcat atgaaataat ttctcaattc 660 ctactctgtc atagcttaaa tgacttactg attaaaatat gagtaacaat aattctggag 720 ctgaaagaca ttctcaagcc aaaaggtaac attaaacaat gttttacttt aaatttaatg 780 tcatgtaggg tcactaaaaa caaaatgtaa gggataaatg taagtgcata aaacagagat 840 aataccaatt tccacaaata caacttttat tatccaaaat catcttggaa ggactttttc 900 taatatgccc attttctaaa taagattaac catttgatgg gaatatttcc aattgtatca 960 cctccttcct tgactttttc ttcatcaact tagggcctgg gttgtaggca ctgtggctct 1020 ttgggatagt taaatgggtg caatttggct gagaccgccc ctgtcttaaa tggcccaggc 1080 tacagggctt gccaaatggc tttggtttgc aacctcttcc tttgatatcc attgaagaac 1140 acatgtccta ccctcttgat tgcaagcttc tatctgctat tggctatcag gagcataaca 1200 gataagttct aaggtccttc cagttccaaa agccattgac caaccctgtg aggcactatg 1260 agagattgga gattactgag gaatctcttc caataacata tgatatataa aggtaattgt 1320 gattctatga agagtgaata aaaattgaaa acaaaaccaa tcttgtttaa actattaaat 1380 gaagttttaa aaaataatgg agtgggtaga tgtattgcct atcaaattaa aattcaggga 1440 acacgtgtca gttatcacct ttataagtat gatctataag gttgaattaa ctaaagatct 1500 aaccctaaac taagtgagat attactgggt tactaaatat agatgaatgg cttccttttt 1560 cctttaaaga tggaagaatc tcaaaagtat gcctgaatca gaagcagagg actcatgttc 1620 taatgacacg tctgatcatc accctgagtt ccataaagct atagcatatt gtagtagaaa 1680 gtatatcagc atgtgagtgg agagatttaa gggtatagat ctctacgtat ttccagctct 1740 gtcaccaact ggtgacatga ctttgggcag aaactgtctt attgattccc tcgtgccgaa 1800 ttcttgctcg aggccaaatt ccctatagcg aacttattga acaga 1845 125 306 DNA Homo sapien 125 gcggcgccgg gcaggtacat aagtgtcact cgcctaatta aaaacattga gtaaaccaag 60 tttttatata gactaccctt gccatatgat gctctttttc tctaataata tgcagtttaa 120 atcctgagga atcaatgccc agcatttcac cacatctgaa ctctgtgtgg gcattcttca 180 ctcgcctaca aggggtaaac aaggctacca gaacttgaat ttgacttata gggagctacc 240 caggaagggg aaagcccttg ggactttttc caaaacaatc ttctatttga actgttcatc 300 agccaa 306 126 2049 DNA Homo sapien 126 aaaaaaaaaa gtaaaacaaa aataaagtct atgcccatta agacgtcttc taattcagtt 60 gtgattgtct gctcctactt aaaaaaatat ttaagcttga tgtttaatta ttccctttca 120 gcaaatttgg atcagaaaat taaagtatgt gacaagatca ggtcaccttg aatttccaca 180 caatctcaag acactgaata gcaaaaaagt aacattacac agtaatgatt aggatatttc 240 cttagacttt gctggatctt tggtcttaag gtaacatgta aaagtagtga agcctttcct 300 ttcatggccc tgtgcaatgt aacggttttc tgcctcctct tcagctggaa gcgttagtgg 360 tagtatgggc acagaatata tgtacactgg cgatgctgac catgcctccc aggtaccctg 420 gctctgggtt ccttgaccta gggaacaaga ttggatgagg cagatctttg agcccatgtg 480 actatagaat ttgctgatga tataatttta caataacaat ggataggaat tttacctctc 540 tttttattag tttaatatta tttaatatta tgtacataag tgttcactcg cctaattaaa 600 aacattgagt aaaccaagtt tttatataga ctacccttgc catatgatgc tctttttctc 660 taataatatg cagtttaaat cctgaggaat caatgcccag catttcacca catctgaact 720 ctgtgtgggc attcttcact cgcctacaag gggtaaacaa ggctaccaga acttgaattt 780 gacttatagg gagctaccca ggaaggggaa agcccttggg actttttcca aaacaatctt 840 ctatttgaac tgttcatcag ccaaagtagt ccactgaggt gacaaagctt tcagaaatac 900 aaagatggga agataaaggt aacactggcc cacttggggc tttgacattg gattgggtgg 960 actgaataaa cacagcctag gtggcctggg cttgagcctc acttacttct ccttgataca 1020 tagttcctgg tctaccttct gacccttttt ctaaaatagc cagtgtctat ttcactaggc 1080 catttactta caagttccca gcttttaggg aaaaaagagg gaggggggag catctagttt 1140 tgaattagat atacatctta gaagtaatga gctattggca gctgttaaat cagattcagc 1200 cacaaaccag aattctttct tgttgaacaa gaccaatgag ttagatgact ttaataattc 1260 cacttttctc tccctctctt ctcctcttcc tgaaatcaga gagatgagaa actactcttt 1320 gaaatacctc cagaggcgtt ttattgtgtt cctttcccct ccaagcagct ccctttatac 1380 aattttgctc aggcaaccaa ggacagagta tcggcagaaa catggagtgc ttttgtatag 1440 gccacctgta cataaaagtg taattattta tttaattttc ccatttgtat catattaaag 1500 ctttgtacag tgttttaagt tctgttttaa aattattttg tattttattt ttataaccta 1560 gtaataaaat attcattccg catgcaaaaa aaaacacaca cacaacccaa acaaccaaaa 1620 acaaacagaa ccaaaagata gaaaccaaac acagcaacag acagacacaa gagaagacga 1680 aaacaaccac acaaacagca cacacaaccg cagcggagaa ccaacaaagc caaacgcaag 1740 acagcacaac aagggacaaa acacacacgt agcacaaagc agccgcagaa ccgaacacac 1800 atctaaagac aggcgacaac aacatagcag gccgtagcac cgacaaccac taaaccataa 1860 ctatccagcg gagatcagat cacagaagcc gacacagaaa gaaaagcatg tatgcaacgc 1920 atgacaccgc agggcggata aaaacactcg taggcgggac cgccgcagaa cgatcgaagg 1980 ctaacaaaca agctagtaga tcacaagtac gtgaccacgc cctcttatct ataaaggagg 2040 aagagggag 2049 127 286 DNA Homo sapien 127 acatctggtt gcggagaaag gaaaaacttc tcaaagaaga atttgaagtg agctttaagg 60 gttgaatgga atttttactg ttagaggtag agaaatacaa tatcataaag aaagatgtga 120 tccctacaag aggattacgt ggtaagttga aagacattaa acagtccaac ctggtcattg 180 tcaaaactat atacgttggg cacagaactg aagaccaggt gtcaaaggag gatggctctg 240 tcccctttgt gtccccagtg cctaaagcag tgtttggtgc aagctt 286 128 12421 DNA Homo sapien 128 agcccacggg atcgcccacg cgtcggggca ggtcaaggag gaggctgaaa gagcctgagc 60 tgtgccctct ccattccact gctgtggcag ggtcagaaat cttggataga gaaaaccttt 120 tgcaaacggg aatgtatctt tgtaattcct agcacgaaag actctaacag gtgttgctgt 180 ggccagttca ccaaccagca tatcccccct ctgccaagtg caacacccag caaaaatgaa 240 gaggaaaaca aacaggtgga gactcagcct gagaaatggt ctgttgccaa gcacaccaca 300 gagctaccca acagattcct atggagttct tgaattccag ggtggcggat attccaataa 360 agccatgtat atccgtgtat cctatgacac caagccagac tcactgctcc atctcatggt 420 gaaagattgg cagctggaac tccccaagct cttaatatct gtgcatggag gcctccagaa 480 ctttgagatg cagcccaagc tgaaacaagt ctttgggaaa ggcctgatca aggctgctat 540 gaccaccggg gcctggatct tcaccggggg tgtcagcaca ggtgttatca gccacgtagg 600 ggatgccttg aaagaccact cctccaagtc cagaggccgg gtttgtgcta taggaattgc 660 tccatggggc atcgtggaga ataaggaaga cctggttgga aaggatgtaa caagagtgta 720 ccagaccatg tccaaccctc taagtaagct ctctgtgctc aacaactccc acacccactt 780 catcctggct gacaatggca ccctgggcaa gtatggcgcc gaggtgaagc tgcgaaggct 840 gctggaaaag cacatctccc tccagaagat caacacaaga ctggggcagg gcgtgcccct 900 cgtgggtctc gtggtggagg ggggccctaa cgtggtgtcc atcgtcttgg aatacctgca 960 agaagagcct cccatccctg tggtgatttg tgatggcagc ggacgtgcct cggacatcct 1020 gtcctttgcg cacaagtact gtgaagaagg cggaataata aatgagtccc tcagggagca 1080 gcttctagtt accattcaga aaacatttaa ttataataag gcacaatcac atcagctgtt 1140 tgcaattata atggagtgca tgaagaagaa agaactcgtc actgtgttca gaatgggttc 1200 tgagggccag caggacatcg agatggcaat tttaactgcc ctgctgaaag gaacaaacgt 1260 atctgctcca gatcagctga gcttggcact ggcttggaac cgcgtggaca tagcacgaag 1320 ccagatcttt gtctttgggc cccactggac gcccctggga agcctggcac ccccgacgga 1380 cagcaaagcc acggagaagg agaagaagcc acccatggcc accaccaagg gaggaagagg 1440 aaaagggaaa ggcaagaaga aagggaaagt gaaagaggaa gtggaggaag aaactgaccc 1500 ccggaagata gagctgctga actgggtgaa tgctttggag caagcgatgc tagatgcttt 1560 agtcttagat cgtgtcgact ttgtgaagct cctgattgaa aacggagtga acatgcaaca 1620 ctttctgacc attccgaggc tggaggagct ctataacaca agactgggtc caccaaacac 1680 acttcatctg ctggtgaggg atgtgaaaaa gagcaacctt ccgcctgatt accacatcag 1740 cctcatagac atcgggctcg tgctggagta cctcatggga ggagcctacc gctgcaacta 1800 cactcggaaa aactttcgga ccctttacaa caacttgttt ggaccaaaga ggcctaaagc 1860 tcttaaactt ctgggaatgg aagatgatga gcctccagct aaagggaaga aaaaaaaaaa 1920 aaagaaaaag gaggaagaga tcgacattga tgtggacgac cctgccgtga gtcggttcca 1980 gtatcccttc cacgagctga tggtgtgggc agtgctgatg aaacgccaga aaatggcagt 2040 gttcctctgg cagcgagggg aagagagcat ggccaaggcc ctggtggcct gcaagctcta 2100 caaggccatg gcccacgagt cctccgagag tgatctggtg gatgacatct cccaggactt 2160 ggataacaat tccaaagact tcggccagct tgctttggag ttattagacc agtcctataa 2220 gcatgacgag cagatcgcta tgaaactcct gacctacgag ctgaaaaact ggagcaactc 2280 gacctgcctc aaactggccg tggcagccaa acaccgggac ttcattgctc acacctgcag 2340 ccagatgctg ctgaccgata tgtggatggg aagactgcgg atgcggaaga accccggcct 2400 gaaggttatc atggggattc ttctaccccc caccatcttg tttttggaat ttcgcacata 2460 tgatgatttc tcgtatcaaa catccaagga aaacgaggat ggcaaagaaa aagaagagga 2520 aaatacggat gcaaatgcag atgctggctc aagaaagggg gatgaggaga acgagcataa 2580 aaaacagaga agtattccca tcggaacaaa gatctgtgaa ttctataacg cgcccattgt 2640 caagttctgg ttttacacaa tatcatactt gggctacctg ctgctgttta actacgtcat 2700 cctggtgcgg atggatggct ggccgtccct ccaggagtgg atcgtcatct cctacatcgt 2760 gagcctggcg ttagagaaga tacgagagat cctcatgtca gaaccaggca aactcagcca 2820 gaaaatcaaa gtttggcttc aggagtactg gaacatcaca gatctcgtgg ccatttccac 2880 attcatgatt ggagcaattc ttcgcctaca gaaccagccc tacatgggct atggccgggt 2940 gatctactgt gtggatatca tcttctggta catccgtgtc ctggacatct ttggtgtcaa 3000 caagtatctg gggccatacg tgatgatgat tggaaagatg atgatcgaca tgctgtactt 3060 tgtggtcatc atgctggtcg tgctcatgag tttcggagta gcccgtcaag ccattctgca 3120 tccagaggag aagccctctt ggaaactggc ccgaaacatc ttctacatgc cctactggat 3180 gatctatgga gaggtgtttg cagaccagat agacctctac gccatggaaa ttaatcctcc 3240 ttgtggtgag aacctatatg atgaggaggg caagcggctt cctccctgta tccccggcgc 3300 ctggctcact ccagcactca tggcgtgcta tctactggtc gccaacatcc tgctggtgaa 3360 cctgctgatt gctgtgttca acaatacctt ctttgaagta aaatcaatat ccaaccaggt 3420 gtggaagttc cagcgatatc agctgattat gacatttcat gacaggccag tcctgccccc 3480 accgatgatc attttaagcc acatctacat catcattatg cgtctcagcg gccgctgcag 3540 gaaaaagaga gaaggggacc aagaggaacg ggatcgtgga ttgaagctct tccttagcga 3600 cgaggagcta aagaggctgc atgagttcga ggagcagtgc gtgcaggagc acttccggga 3660 gaaggaggat gagcagcagt cgtccagcga cgagcgcatc cgggtcactt ctgaaagagt 3720 tgaaaatatg tcaatgaggt tggaagaaat caatgaaaga gaaactttta tgaaaacttc 3780 cctgcagact gttgaccttc gacttgctca gctagaagaa ttatctaaca gaatggtgaa 3840 tgctcttgaa aatcttgcgg gaatcgacag gtctgacctg atccaggcac ggtcccgggc 3900 ttcttctgaa tgtgaggcaa cgtatcttct ccggcaaagc agcatcaata gcgctgatgg 3960 ctacagcttg tatcgatatc attttaacgg agaagagtta ttatttgagg atacatctct 4020 ctccacgtca ccagggacag gagtcaggaa aaaaacctgt tccttccgta taaaggaaga 4080 gaaggacgtg aaaacgcacc tagtcccaga atgtcagaac agtcttcacc tttcactggg 4140 cacaagcaca tcagcaaccc cagatggcag tcaccttgca gtagatgact taaagaacgc 4200 tgaagagtca aaattaggtc cagatattgg gatttcaaag gaagatgatg aaagacagac 4260 agactctaaa aaagaagaaa ctatttcccc aagtttaaat aaaacagatg tgatacatgg 4320 acaggacaaa tcagatgttc aaaacactca gctaacagtg gaaacgacaa atatagaagg 4380 cactatttcc tatcccctgg aagaaaccaa aattacacgc tatttccccg atgaaacgat 4440 caatgcttgt aaaacaatga agtccagaag cttcgtctat tcccggggaa gaaagctggt 4500 cggtggggtt aaccaggatg tagagtacag ttcaatcacg gaccagcaat tgacgacgga 4560 atggcaatgc caagttcaaa agatcacgcg ctctcatagc acagatattc cttacattgt 4620 gtcggaagct gcagtgcaag ctgagcaaaa agagcagttt gcagatatgc aagatgaaca 4680 ccatgtcgct gaagcaattc ctcgaatccc tcgcttgtcc ctaaccatta ctgacagaaa 4740 tgggatggaa aacttactgt ctgtgaagcc agatcaaact ttgggattcc catctctcag 4800 gtcaaaaagt ttacatggac atcctaggaa tgtgaaatcc attcagggaa agttagacag 4860 atctggacat gccagtagtg taagcagctt agtaattgtg tctggaatga cagcagaaga 4920 aaaaaaggtt aagaaagaga aagcttccac agaaactgaa tgctagtctg ttttgtttct 4980 ttaatttttt ttttttaaca gtcataacca ctaatgggtg tcatcttggc catctaaaca 5040 tcatcaattt ctaaaaacat tttccttaaa aaattttgga aattcagact tgatttacaa 5100 tttaatgcac taaaagtagt attttgttag catatgttag taggcttagt tttttccagt 5160 tgcagtagta tcaaatgaaa gtgatgatac tgtaacgaag ataaattggc taatcagtat 5220 acaagattat acaatctctt tattactgag ggccaccaaa tagcctagga agtgccctcg 5280 agcactgaag tcaccattag gtcactcaag aagtaagcaa ctagctgggc tcagtggctt 5340 atgcctgtaa tcctagcact ttgggaggct gaggtaggcg gattgcttga ggccaggagt 5400 tcaagaccaa cacggccaat gtggcgaaac cccgtctcta ctgaaaaata caaaattagc 5460 cgggtgtggt ggtgggtgct tgtagtctca gctacttggg aggctgaagc aagagaattg 5520 cttgaatcca ggaggaggag gttgcagtga gcccagatca tgccactaca ctccagcctg 5580 ggtgacagag tgaggcactg tctcaaaaaa aaaaaaaaaa aaaaaaaaga tactgaacta 5640 ggcacttgac atccaagatg tccacttggc ccttttctaa gtgtacttca ctttgttttc 5700 attcctcctc taaagctttt taacaaactg tcactcatgt tctaaaaaca aacaaatgtc 5760 tttcatctca ttttttactc agcattatct atcaaaggga ctggatgtcc catctagttt 5820 gtactttagt ttctagctca ttacatagga aatgcaaata aaaaacacaa tgagatacca 5880 cttcacaccc actaagatgg ccataactta ttttttttaa aaaaaggaaa aggaaaataa 5940 taagtgttgg tgaggaagtg gacagaaatt ggaattctca tacattgctg gtgggaatgt 6000 ggaatggttc aactgctgtg gaaaacagtt tgtctgttcc tcaaaaagct aaacatagaa 6060 ttaacatatg acccagcagt tccactccta gatatatacc caagagaatg caaaataggc 6120 attcaaacaa atacaggtac acaaacattc atagcagcac tattcccaat agccaaaagt 6180 cagaaacaac ccaaagtcca tcaatgaatg agtggataaa taaattgtgc tataaacaca 6240 taatacaatt ttatttggcc ataaaaatga agtgttgata catgctacta tgtaaataaa 6300 tctcaaaaac ttgtactaag tgaaagaagc cagacacaaa aggtctcata caattcgatt 6360 tatataaaat agcaagaata gataaaacca tagagacaga aagcagattg gtggttgctg 6420 ggggctggag gaaggaagga atggagagta tctgcttaat gggatggggt ttccttttag 6480 aggagaacat tttttttgga actttaaata aaggtggtgg ttatgcaaca ttgttaacaa 6540 tactaagtgg cactgaactt ctcactttaa aatagttaat tttatgttat gtgaagttta 6600 cctcaataaa aaaattctta aaaaaaaaaa ctcagtgata tccaaccatt aaaaaatata 6660 agttacatag ctcgtatata atcaacttac ttattactgc actatgaggg gcacccagat 6720 atgtaagaca gagtcccaac ctttggttgt tggaggacta tctaaggata cagagattaa 6780 taaaaataaa agaactacca cgaaagaagt gccctccaag tacaaagaga gttcaaatat 6840 gtacatctgg ttgcggagaa aggaaaaact tctcaaagaa gaatttgaag tgagctttaa 6900 gggttgaatg gaatttttac tgttagaggt agagaaatac aatatcataa agaaagatgt 6960 gatccctaca agaggattac gtggtaagtt gaaagacatt aaacagtcca acctggtcat 7020 tgtcaaaact atatacgttg ggcacagaac tgaagaccag gtgtcaaagg aggatggctc 7080 tgtccccttt gtgtccccag tgcctaaagc agtgtttggt gcatgcttgg tgattggtaa 7140 atgtcaaaga aaaagataaa agataaaata tagccgggcg cggtggctca agcctgtaat 7200 cccagcactt tgggaggccg agcttaacat tgagaaaaga aaggaaatgc aacaagaaaa 7260 gcagaaagca cttgatgtag aagcaagaaa gcaggttaac aggaagaaag ctttactgac 7320 tcgtgtccag gagattcttg acaatgttca ggttagaaaa gcacctaatg ccagtgattt 7380 tgatcagtgg gagatggaaa cagtttactc taattcagaa gtcagaaact tgaatgttcc 7440 tgctacattt ccaaatagct ttccaagcca tacggaacac tctactgcag caaagcttga 7500 taagatagct gggattttgc cattggataa tgaggaccaa tgtaaaactg atggaataga 7560 cttagctaga gattcagaag gatttaattc tccgaagcaa tgtgatagtt ccaatattag 7620 tcatgtagaa aatgaagctt ttccaaagac ctcttcagca accccacaag aaactcttat 7680 ttctgatggt cccttctcag taaatgaaca acaggatcta ccacttttgg cagaagtcat 7740 cccagatccc tatgtaatga gtcttcagaa tctgatgaaa aagtcaaagg aatatataga 7800 aagagaacaa tctagacgca gtctgagagg tagtatgaac agaattgtta atgagagtca 7860 tttagacaaa gaacatgatg ctgttgaagt ggctgactgt gtaaaagaga aaggccagtt 7920 gacaggcaaa cactgtgtct cagttattcc tgacaaacca agccttaata aatcaaatgt 7980 tcttctccaa ggtgcttcca ctcaagcaag cagcatgagt atgccagttt tagctagctt 8040 ttcgaaagtg gacataccta tacgaactgg ccatcccact gttctagagt ctaattctga 8100 ttttaaagtt attcccactt ttgttaccga aaataatgtt atcaaaagtc ttacaggttc 8160 atatgccaaa ttacctagtc cagagccaag tatgagtcct aaaatgcacc gaagacgttc 8220 caggacatca tcagcgtgtc acatacttat aaataaccca ataaatgcct gtgaattaag 8280 ccctaaagga aaagaacagg caatggactt aattattcaa gatactgatg aaaacacaaa 8340 tgtgcccgaa attatgccaa agttaccaac tgatttagcg ggagtttgtt caagcaaggt 8400 ttatgtgggc aaaaatacat ctgaagtcaa agaagatgtg gttttaggta aatcaaatca 8460 ggtatgtcaa tcttcaggaa atcatttaga aaataaagtt actcatggac ttgttactgt 8520 ggaaggtcag ttaacatccg atgagagagg cgcacacata atgaacagta cctgtgctgc 8580 gatgccaaag ctgcatgaac catatgccag cagtcagtgt atagcaagtc caaactttgg 8640 aactgtgagt ggactcaagc cagccagtat gttagagaaa aactgcagtt tgcaaacaga 8700 actgaataag tcttatgatg taaaaaaccc ttctccttta ttgatgcaaa accagaatac 8760 gagacagcag atggacacac ctatggtgtc ctgtggaaat gaacaatttt tggataacag 8820 ttttgagaaa gttaaacgga gacttgattt agatattgat ggtttgcaaa aagaaaactg 8880 cccttatgtc ataacaagtg gaataactga acaagaaagg caacatttgc cagaaaaaag 8940 ataccctaag ggatctggct tcgttaacaa gaataaaatg ttaggaacta gttccaaaga 9000 aagcgaggag ttactaaaaa gcaagatgtt agcttttgaa gaaatgcgga agagactaga 9060 agaacagcac gcccagcaat tatcactact catagctgag caggaaaggg aacaagaaag 9120 actgcaaaag gtttttagtc tggaaataca agcaaaattt aacaaaataa ctgcagtggc 9180 aaaaggattt cttactcgta gacttatgca gacagataag ctgaagcaac ttcgacaaac 9240 tgtaaaattg cgagctgcct tgtacggtat tcatgacata ttctttgtaa tggatgcagc 9300 tgaaagaatg tctattctac atcatgatcg agaagttcgc aaagagaaaa tgctcaggca 9360 aatggataaa atgaaaagtc cacgagtggc tctttcagct gcaacacaga agtctcttga 9420 taggaagaaa tacatgaatg ttgggaatag caggtacgag tggatatact ttcctactca 9480 tactgagctg aacactggag ggcccgttct ggagatgatc cttttccctg tcataggtca 9540 ccatctcatg aacaaccaca gaccaccacc cccgaatgaa aacatggcgt ctgcagaagg 9600 tgctgtgcgg ccgctgcggg gcggccagct gcccttcaca aacatggcgg ccgaggggtg 9660 cggggagtgg cggggtaagg atgggaagcc gagcagacgg ccccagaaca agcggtcatg 9720 tgactgggaa gatggccgtc tttccttgtt tattattaag gatattacaa agaatacaga 9780 tgaacagcca gatgaagagc tacgtagggt cacagagtca aagacaaaga aagtgaaccg 9840 gaaaggaagc acttcttcca cgtcctcctc ctcctccagc tccgtggtgg acccgctgag 9900 cagcgtcctc gatgggactg accccctctc catgtttgca gccactgctg accccgcagc 9960 cttggcagct gccatggaca gctccagaag gaaacgtgat agagatgata actccgttgt 10020 aggatcggat tttgagcctt ggaccaacaa acggggagaa atccttgccc ggtacaccac 10080 taccgaaaag ctgtctatta atctgtttat gggatctgaa aaaggcaaag ctgggactgc 10140 cacattggca atgtcagaga aggtgcggac ccggctggag gagctggatg actttgagga 10200 gggttcccaa aaggagctgt tgaacttgac tcagcaggat tacgtgaacc gcatagagga 10260 gctcaaccaa tcgctgaagg atgcctgggc ctcagaccag aaagtgaagg ctctaaaaat 10320 agtcatccag tgttcaaagc ttctttcaga caccagtgtt attcagttct acccaagcaa 10380 atttgtcctt atcaccgaca tacttgatac atttggaaag ctcgtgtacg agcgcatctt 10440 ttccatgtgt gtggatagcc gcagcgtctt accaggatgt ttttgtagtt acgtggaggc 10500 atccatcctg aaatgtaaca aattcctctc caaaacggga atttcagagt gcctgccccg 10560 gttgacatgc atgatcagag ggatcggaga cccactagtg tcggtgtatg cccgtgccta 10620 cctgtgccgg gtgggaatgg aagtggcccc acatctcaaa gaaaccctaa ataagaactt 10680 ttttgacttc ctccttacgt tcaaacagat tcatggggat acggtccaga accagctggt 10740 ggtccaagga gtggagctcc catcttacct ccccttgtac ccgcctgcca tggactggat 10800 cttccagtgc atctcctacc atgcccccga ggctctgctg accgagatga tggaaaggtg 10860 taagaaacta ggaaacaatg ccttgctgtt gaattctgtg atgtctgcct tccgggctga 10920 gttcatcgcc acaaggtcta tggatttcat tggcatgatt aaagagtgtg atgaatctgg 10980 tttccccaag catcttcttt ttcgatcact gggattaaac ttggccttgg ctgatcctcc 11040 tgagagtgac cgacttcaga ttctcaacga agcttggaaa gtcatcacta agctgaagaa 11100 cccacaggac tacattaatt gtgccgaagt gtgggtggaa tacacctgca agcatttcac 11160 gaaacgagag gtgaataccg ttttggcaga tgtcatcaag cacatgactc cagatcgtgc 11220 atttgaagat tcctaccccc agcttcagtt aataattaag aaagttattg cccacttcca 11280 tgacttctca gttcttttct cagtggaaaa atttctgccg tttctggaca tgttccaaaa 11340 agagagtgtg cgggtggagg tttgcaaatg catcatggac gcctttatca agcatcaaca 11400 agagcccacc aaggacccgg tcatcttgaa tgcccttttg catgtttgca agaccatgca 11460 tgactctgtg aatgcactca ctcttgagga tgagaaaaga atgctgtcat atttgattaa 11520 tggatttata aaaatggttt cctttggccg tgattttgaa caacagctga gtttttatgt 11580 tgagtccagg tcgatgtttt gcaatctgga gcctgttctt gtgcagttga ttcatgcctg 11640 tgttgcctac tgcttcatca ccatcccctc cctggcgggc atcttcacac gtctcaatct 11700 ctacctgcat tctggtcagg tggccttggc caaccagtgc ctctcccaag ctgatgcttt 11760 tttcaaagcc gctataagcc ttgttccgga agttccaaag atgattaata ttgatgggaa 11820 gatgcggcca tcggaatcgt tccttctgga attcctctgc aatttctttt ctactttatt 11880 aatagttccg gatcatcctg aacatggggt cctgtttctt gttcgagagc ttctcaacgt 11940 gatccaggac tacacctggg aggacaacag cgatgagaaa atccgcatct acacctgcgt 12000 cctgcatctc ctctccgcca tgagccagga gacgtacctt taccacatag acaaagtgga 12060 ctccaacgac agcctctacg ggggagactc caagttcctg gcagaaaaca acaagctgtg 12120 tgagacggtg atggctcaga tcctagagca tctgaaaacc ctggccaagg acgaggccct 12180 gaagcgccag agctcgttgg gcctttcctt ctttaacagc atcttggccc atggggacct 12240 acgcaacaac aagctcaacc agctctccgt caacctgtgg cacctggcac agaggcacgg 12300 ctgtgcagac accaggacca tggtgaaaac gctagaatac atcaagaagc aaagcaaaca 12360 accagacatg actcatctga cggagctggc cctcagactc cctctgcaaa caaggacctg 12420 a 12421 129 1494 DNA Homo sapien 129 cggccgccgg gcaggtacta ggttctgaca tcagtgaagt agcttccatt tcatttctct 60 gagtgcttca ctcagcaaga gactatgcga caactacgtg ctgggtgttc cagatgtatt 120 gaactctgga caaactgctt gacttcagcc tcttgaacta ttgttaatac acgggcagct 180 tgttatatag ctcccattgg tatacaactt gctaattaaa tggaaaatac ccttgggccc 240 acgtgccatt gtgcttgtgc tatacaacca tggtaaattc cccaggcatt ttattgggcg 300 cagtgtccac atgggccgtg tgttggtatt caacccttgg aagtgctcag gggaagattc 360 tgaagaaacc cattccttag tcgccaaagc gattggtttg acatgcccgc cggctctatt 420 ctaacctaac agacagaatt acggaagaca ttttatgtgc ttgttgtgtc cgctatgtgt 480 ttgtggctgc ggtgacaaac ccagttgcta aacacatacc ttccaaggcc tttacctttt 540 gcaacgcaat gtggcctttg cacacaagta ctggagaggg aagattaccg aactatatga 600 aaacccctct gtgcggaacg gtggcccatg gaacttggct atttggccac atggctagtt 660 aaggccacct aaaacggcaa aattttgggt tggtcgccta agcgtttggt caaatcagtt 720 gcccctaatg tggccctttg ggtgcacggt caactttatc cgccgaagtt tccgattcgt 780 aatagaatcg tagcatcatg acatgaaacg acacacacac acacaaaaca cactacaata 840 gcagcgctca ctgatgcagc gagcggtaaa taaccaccct ccgacagaga ggggcggacc 900 gaccacaaaa tagagacgca gtgtagagta ctacacacca cccaggttgt tagttgggta 960 gtgcagacac aacattcttc ttgtgaatat aaagcattcc cgcgagtgat ccttcctact 1020 accagtatta tcatccctac tcatgctatg gctacatcgt gcaacaatta ttcatgcacg 1080 tgcgagtgat agcgacacaa acatacggtg atacatctaa ctagacgcta acgcacatca 1140 gcatccaacg agaatatatt atgaacagat ggagcacgac tgaagtcgta ggttgattcg 1200 cacatgctgg acgtatgagt atccggagat gtcaactgac aggagtgcat gtgggcacag 1260 ggcttacggc agtagtagca ccatacggct gacctagaga tggattggta aatcaaagta 1320 gtgagggagc ggcggaatgg gaagcgtgac ggggatgtga tgttagctgt cggagttgga 1380 cggagggagg catgggagga acgtgtgagc aatagagccg gcgaggtgtc tacaggaagg 1440 gagagcagag gcgagcacgg agcgatcgct ggagctgcag ctgcccaggc ggcg 1494 130 1774 DNA Homo sapien 130 tgtgagttcc acagaagatt tcagttgaaa agcactatta atgtttccta ctgtggacag 60 catttagagg aaacatttta agcagcacgt tcatatttcc tctgttcacg tacttagtca 120 acagctcttc attgtgcgct tatcgtgtgc aaggcagtgt tctacatgct atggggtaaa 180 caagatgaca aatccctgtc cccttagaaa agagcttgca accacagtgg ctgttggaaa 240 gaagcaacag tggtgctaaa agacaccagg taaactggaa aggaaaattc atcatatagc 300 gtactaggtt ctgacatcag tgaagtagct tccatttcat ttcttgaggc ttcatcagaa 360 gagatatgcg acaatacgtg ctgggtgttc cagatgtatt gaactctgga caaactgctt 420 gacttcagcc tcttgaacta ttgttaatac acgggcagct tgttatatag ctcccattgg 480 tatacaactt gctaattaaa tggaaaatac ccttgggccc acgtgccatt gtgcttgtgc 540 tatacaacca tggtaaattc cccaggcatt ttattgggcg cagtgtccac atgggccgtg 600 tgttggtatt caacccttgg aagtgctcag gggaagattc tgaagaaacc cattccttag 660 tcgccaaagc gattggtttg acatgcccgc cggctctatt ctaacctaac agacagaatt 720 acggaagaca ttttatgtgc ttgttgtgtc cgctatgtgt ttgtggctgc ggtgacaaac 780 ccagttgcta aacacatacc ttccaaggcc tttacctttt gcaacgcaat gtggcctttg 840 cacacaagta ctggagaggg aagattaccg aactatatga aaacccctct gtgcggaacg 900 gtggcccatg gaacttggct atttggccac atggctagtt aaggccacct aaaacggcaa 960 aattttgggt tggtcgccta agcgtttggt caaatcagtt gcccctaatg tggccctttg 1020 ggtgcacggt caactttatc cgccgaagtt tccgattcgt aatagaatcg tagcatcatg 1080 acatgaaacg acacacacac acacaaaaca cactacaata gcagcgctca ctgatgcagc 1140 gagcggtaaa taaccaccct ccgacagaga ggggcggacc gaccacaaaa tagagacgca 1200 gtgtagagta ctacacacca cccaggttgt tagttgggta gtgcagacac aacattcttc 1260 ttgtgaatat aaagcattcc cgcgagtgat ccttcctact accagtatta tcatccctac 1320 tcatgctatg gctacatcgt gcaacaatta ttcatgcacg tgcgagtgat agcgacacaa 1380 acatacggtg atacatctaa ctagacgcta acgcacatca gcatccaacg agaatatatt 1440 atgaacagat ggagcacgac tgaagtcgta ggttgattcg cacatgctgg acgtatgagt 1500 atccggagat gtcaactgac aggagtgcat gtgggcacag ggcttacggc agtagtagca 1560 ccatacggct gacctagaga tggattggta aatcaaagta gtgagggagc ggcggaatgg 1620 gaagcgtgac ggggatgtga tgttagctgt cggagttgga cggagggagg catgggagga 1680 acgtgtgagc aatagagccg gcgaggtgtc tacaggaagg gagagcagag gcgagcacgg 1740 agcgatcgct ggagctgcag ctgcccaggc ggcg 1774 131 531 DNA Homo sapien 131 ccgaggtact taattctttg gcaacaaaca gcaagttttt atggtttaat tgtatttcct 60 ctctagagat cacaatactc tgggtatttt atatcccttc taaaggtcat ttgggttttc 120 aaatgggaag aatagtcaag ctaagctgga ctaaacctaa gtaatatttt atctcatcaa 180 aagaagttat taatctaact gggttagcat gagtcattca ttttttagac atgataaatg 240 ggaaacatat caaatcatta gataaattct gacctggaat tgaattcccc ctttcttaaa 300 atctttttaa tttgcttttt tcatagactc agtatggaac tcttaactga taagggagag 360 attcttgatc tggaaccgtt ccctgccatt ctcctttttt ctctctgtct aggtagctgg 420 ttccatagtg cccgtcacga gggtccattt cagtttgatg acattagact gcttacactc 480 agctggatgc cttgctgttt gcagcaacat gattttacag tatgcttttc t 531 132 4309 DNA Homo sapien 132 tggggcatga agttctgcca ctaaggcata accagtaccc aagtaggaaa ggattattga 60 tccctggagt aaagattcct agcttgcggg gatctcacta ttgatccccc ggagtaaaga 120 ttcctagctc gcaggaatct tacttgcaca cttaaggaaa ataccagagg gagccactag 180 caaccgaaaa atgaaggaaa gatttaattt ctctacccag gtacaaatcc aatgcatagt 240 atagtatatg ttatatgcag aaagggcact ggaggtgtga gagccctttg ggtaacagct 300 ctgctagttg ttaccttcac acttctcttt cttcttaatc tctggtttct cgtctgaaaa 360 atgagataat tggactagat taatagttct cagccttttc tagaacaaca aattagatta 420 tctctgaagt ccttttccaa aatttcatgc ttccagtctc tccccgtgat tgcatattat 480 ccctaggcta attaaaagtg tgctggttaa tcagtttctt tacttttttt tctctctttt 540 ttttattctg tgttcaggta tcatttgacc aacaacttgc tcttaatctt actgcgatga 600 ctgaaatctc caaagaggag agtatagtag ttataggtct agtaataata atcttgtaaa 660 caattcatta ttttttaaaa cttaatgctg tgtgcctaat cagtgttgag tatgactaaa 720 atgtaaatga gaaccaaata tgacactaac gctggcacta aattttattt ttacttgtgt 780 acttaaagta ctttactggc ctgttgggaa attgatttgt ataagattca cacctggttt 840 tggcagaaac agctttttaa agatacaatt aggctgactt aaaaatgttt tttattccac 900 agaatgtatc tttattatgt cattcttacc gtctctctgc cttttttgac catcatgtaa 960 ctacgcagta gtaaatcatg gggtgcaggc tgatgaatta gtagtctttg taaaactaaa 1020 atgtaatgag cataggaaga gacagctctt ctggtgaaca tggcagtttt ccggtaatac 1080 cagccttgat gaataggcta aagacagctg tgtactatgg acattcaact tcactggatt 1140 gcctggctta gcttttcagt tattgtcttg ccgtgaaaca tggtgttgca ctgtacacat 1200 tttagaatag tggcaagaat gttctttaga actgcagata acccaacaga gaataccata 1260 ccaatatatc ggtttctcct gttacataga gatttggtat ttcagtgatg gttatggttt 1320 ttgactcacc tgtgtgtcag tcctgctaga gagacagtat agaatcaaga atttcttgat 1380 gtctttttaa aaatagagat tataatggcc ttgctagttg tcctgtgaag tgacagaccc 1440 ttaattagaa atcttttaat cctgctttcc attttacttc tccaccattt atttttaaca 1500 ttcattctct gaaaatagtt atgattttta gtgtaattgg ctatgtttaa gaaattccat 1560 ttcaaagtct taatatgtaa caatcttcat tttttataaa attgaaggac atttttgagg 1620 caaacttact tttatagctc attttctccc tagttaagga gaattctctg gtttcatata 1680 gagaatggct agctctgtga taccccaccc tctttgtggc ctaccagttg ctgttgtgtt 1740 gcttaaaatt gcagatattc tcataaacat gatgattttt ggcacaggcc tttctttgct 1800 attgatttca aaataaagtt gggcaatccg atttgaacta ctttaataaa cataatttag 1860 cattcctgta atgagaaagt attttcaaaa gataaccaga tttatttcta ggattagaga 1920 tggcaaatac caatgatagt atttttccca agagcaatca cagattaatc tataaatatg 1980 agaagtcgca ttattgtact taattctttg gcaacaaaca gcaagttttt attgtttaat 2040 tgtatttcct ctctagagat cacaatactc tgggtatttt atatcccttc taaaggtcat 2100 ttgggttttc aaatgggaag aatagtcaag ctaagctgga ctaaacctaa gtaatatttt 2160 ttctcatcaa aagaagttat taatctaact gggttagcat gagtcattca ttttttagac 2220 atgataaatg ggaaacatat caaatcatta gataaattct gacctggaat tgaattcccc 2280 ctttcttaaa atctttttaa tttgcttttt tcatagactc agtatggaac tcttaactga 2340 taaggagaga ttcttgatct ggaaccgttc cctgccattc tcctgttttt ctctctgtct 2400 aggtagctgg ttccatagtg cccgtcacga gggtccattt cagtttgatg acattagact 2460 gcttacactc agctggatgc cttgctgttt gcagcaacat gattttacag tatgcttttc 2520 tcaaagcttt gcattcttaa tggagatatc aaatggtgta attccaaata taaatatgtt 2580 tatgacacta atcatatgct tttaacaata actttttgat aacttattgc cctgtaagtt 2640 aaaccttaca cggagtgact gttgccatca gaaaatcccc tttcacctgc tagagagagt 2700 gaaagtagtg cgtggcctcc acttttcagt taacgagtag caagcttcta gtaggggctg 2760 cttatctgac ccatgtgggg tcttgggcct tgttactttc ctgggttcgt cccttcagct 2820 ggaaaggctg ttgaaaacac ttgccaggaa acagtaaagc tgtgagagaa tcttctagtc 2880 ttagatatag agaaatgagt accagttgat gctaacacga tacttagact ttgaggggct 2940 tccatccaag ctttggcatg aatctgttag acacggtttt cttcactcct ctgataatct 3000 ttttttccag aatggttttt tgttgttgtt gttgttaaca aattctaaac atccagtgtt 3060 actttttgtt ttgtttgttt tgttttgttt tgttttgttt tgtttgccct tcaggaaagt 3120 cctttttcga gtaggtattg attgttccct ggaaactctc agcagtgtct gtgcaggctc 3180 tgtgcatgct ttgtatgagt tcggcttgaa caatgcattt gaagtcacct gggatgtcca 3240 gttctggcat gtcttcattg attgtgtttt taaacatgtt tcatgtttca tgtcattttc 3300 caaacctcac tttacatctt actcagagaa gttaatcaag gaatgaaatt tctaggggga 3360 tagggatgat gagggtgggt tgggggcttg agtgaagtca acttggggta tttgctttaa 3420 agtgttttct aaagcagttc ctaacagtat ttagagattc cctgggatgt ttgtggctca 3480 acttattctg gacaaagtgt gtgtgggggt ggtcttactg agatttgcat tcttaatgca 3540 ggacaggctc taaatttcat ctgtactcta aatttgtgat tgaatccaag aagataacag 3600 agacagtgct cctgttgtaa tgtttctggc aagtgctccc taaaatgcac atcgaattct 3660 gttttctggg ccttttctcc aatggtgcta ggagataccg ttgatttctg cagctcttct 3720 cagtggtggg aagaagtctt tgggattgtt gagcaagggg cagctggacc atccactaaa 3780 tttttttgtt caagacacat tagagaccct cctgtatatc tagtaagtca taataaaggt 3840 gcttgggaaa gccttaaatt tgaagacaca tggaggcggt agaaaattaa acttgtaaga 3900 ggagaaaaac atgccattag gtaacgcaga gttgtaacta ctggctaaga ctcaatggaa 3960 cttccacttg ctctaaaacc agggaaggga gtgggacgat aagtcttttg aagacatcag 4020 ctcactgtgc tgagagaggg accaaactca aggaaacctc tgatctatac attcaactgc 4080 tgcatttttt tataaataca tgtaaatgtc ctgttgtaat atttgatctt ggaaataaaa 4140 acaaaaactt ttcgtagaaa aaacacacac gacaaaaaca aaatttgggg ggccggcgcc 4200 aagaagtttc aaccacatgt gtggggccgg cccaggtgaa ggaaatggca agtggccaag 4260 aaccggccag aaggggggtt tcccaaaaaa cgcgcgggcg cgcgtttga 4309 133 730 DNA Homo sapien 133 gccgccgggc aggtacaacg tggagatttc cctctgggaa aatcacccag caagtgaaat 60 ccgacccaga gggggacaca ggagtgctcc cgtgggacag cgtggccacc actgggaggg 120 gctctggcag tttttcttgt tttttacgct gcgatgtctg tgaatcttga gagcccagct 180 gatgcgttgt aacctcacct gggggcgatg tggaacattc caggcctggc aggggctatg 240 cctgccatgc agacctcacc cgagccatct caccctgggt ctgtcagagt cccacgtgct 300 gtcgcccctc acccaccccc gacggggcca tgctcctggt catgctgtga ttcattcatc 360 attccatggg caggtgtggg attgtctctg tgtttctgtc tgctttttaa agaagatgag 420 gtaagcatgg aaaacaaaac aaacgtggta accccatcac tcagacgtgt ccactgttag 480 cattcgggaa caggtgagag cagtctggcg cacaggtttt aaggctggct ggcccagact 540 ttggtcttgt gctgtgtgat cttggggaaa tcactgattt ctgagccttt ttcccagctg 600 ctttttctct tggggctggt agaaggaata agagagtgag tgtcaaaaaa aaaaaaaaaa 660 aaagcttggg gttaatcatt ggcaaatatg ttcccggtta aaattgtttc ggtcaaatcc 720 atttggagaa 730 134 226 DNA Homo sapien 134 gcccgggcag gtactgggtt gcagcaagct atgatgccct gaggttccct gaagacaagt 60 aagaacacac tcaacttgtc actcagaaac gcagccctta aaggcttcca gataagaata 120 atgactgggt aaagccaggc tgccacctaa gctgaagcta caggtaggtg actaaggaaa 180 cactgatgtc aggccagcct aggccaactt ctccatgtgt tctttg 226 135 937 DNA Homo sapien 135 tttttttttg agatggagtc tcgctcaagt gcccaggcta gagacagtgg ctcaatctca 60 gctcactgca acctccgcct cctggattca aacgattctc ctgcctcggc cttctgagta 120 gctgggatta caggcatgcc ccaccacgcc cggctaattt ttgtattttt ggtagagatg 180 gggtttcacc atattgtcca ggctggtctc aaacccctga cctcaggtga tctggccacc 240 tcagcctttc aaagtgctga gattataggc gtgagccact gtgcccagcc gcagaaaagc 300 ttcttacctt gagcaggggc atctctcggg cctgctggat taaaaggtgc atttcgttga 360 tctgctgccg cacaaggggc ggtactgggt tgcagcaagc tatgatgccc tgaggttccc 420 tgaagacaag taagaacaca ctcaacttgt cactcagaaa cgcagccctt aaaggcttcc 480 agataagaat aatgactggg taaagccagg ctgccaccta agctgaagct acaggtaggt 540 gactaaggaa acactgatgt caggccagcc taggccaact tctccatgtg ttctttgcga 600 caccaagctt taagtggatc cctcttggag cctgactccc acaatcaggg agagctgaaa 660 gtaagtgcca cagcactgtg gattctcaat tccgcagggg gcaaccaacg ggctgtggat 720 tttcattctt gcttatactt caatcaagat cacaaaacgt ttaagatcat gagctgcttt 780 aatttggaag aaagtacaga tgacagaatc tgggacattt tcttcccttg caagtagatg 840 ctataaggct cagagactta aaataaactc aaactaaggc ataatcattg aaatgattcc 900 agttcagaag ttttagtgct taaatggcag cctgagg 937 136 96 DNA Homo sapien 136 gcccgggcag gtaccaatca attttgaaaa tgaaagggaa aatacttatc tttcctatat 60 gaattgggaa aataaaagga tatgaaaagg taaata 96 137 151 DNA Homo sapien 137 aaaatgtagg cagcaaaagt ggaagaggag aggcagctgg tgcactaatc caggtgagag 60 gtaaagatgg atgggtaggg ctgaaggatg gtggggcagg tggtgagaag tgacttggtt 120 ctggagacat atgaaggaag atggtcaggc a 151 138 604 DNA Homo sapien 138 cgtggtcgcg gcgaggtact ttcttagacc agtgtaacct cacacctcag tttggctttt 60 ccaaccctga cttgaaaggc atatttgtat ctttttatta gtgatagtga agctgtgaca 120 ctaacctttt atacaaaaga gtaaagaaag aaaaactaca gcgattaaga tgagaacagt 180 tctgcagttg ttgaactaga tcacagcatt gtaggcagaa taaaaaatgt tcatatctga 240 gaatattcct ttcgccatct tttcccaagg ccagacctcc tggtggagca cagttaaaag 300 taacattctg ggccttgtaa tcggagggct gtgtctccag ctggcagcct tgttttaata 360 tataatgcag gactgtggaa aacagttggc atagaatatt ttcacctaaa aaagaaagaa 420 aagacataca aaactggatt aattgcaaaa agagaataca gtaaaatacc atataactgg 480 acaaagctag aagaaccttt agaagatttg tctgaaaaca gatttcaaga gtgagctttt 540 atacactgct cactaatttg cttgattact accaactctt cttaaagtta acacgtttaa 600 ataa 604 139 4461 DNA Homo sapien 139 tgagttttcc cctgttggcc agggatggtc tcgatctcct gacctcgtga tctgtccacc 60 tcggcttccc caagtgctgg gattacaggc atgagccacc gcgcccagcc tagccatatt 120 tttatctgca tatatcagaa tgtttctctc ctttgaactt attaaccaaa aaggaacatg 180 cttttcatac ctagagtcct aatttcttca tcatgaaggt tgctattcaa attgatccat 240 cattttaatt ttaccaatgg ctcaaaaatt ctgttcagta aatgtctttg tgactggcca 300 atggcataaa ttatgtttaa gattatgaac ttttctgaca gttgcagccc atgttttccc 360 tacgatacca gatttccatc ttggggcata ttggattgtt gtatttaaga ccgtcagaat 420 aatgatagtg tgtggtctcc agaggtagtc agaatcctgc tattgagttc tttttatatc 480 ttccttttcc attttttatt accattttgt ttgtttagac tacactttgt agggattgag 540 gggcaaatta tctcttggag tggaattcct gtgttttgag ccttacaacc aggaaatatg 600 agctatacta gatagcctca tgatagcatt tacgataaga acttatctcg tgtgttcatg 660 taattttttg agtaggaact gttttatctt gaatattgta gctaactata tatagcagaa 720 ctgcctcagt ctttttaaga aggaaataaa taatatatgt gtatgaattt atatatacat 780 atacactcat agacaaactt aacagttggg gtcattctaa cagttaaaac aattgttcca 840 ttgtttaaat ctcagatcct ggtaaaatgt tcttaatttg tctgtgtaca ttttcctttc 900 atggacagac cattggagta cattaatttt cttaatctgc catttggcag ttcatttaat 960 ataccatttt ttggcaactt ggtaactaag aatcacagcc aaaatttgtt aacatcaaag 1020 aaagctctgc catatacccc gttactaaat tattatacat ccagcagatt ctgggatgta 1080 ctaacttagg gttaactttg ttgttgttga taatactaga ttgctccctc tttaattctt 1140 cttctggtgc aaggttgctg cttaagttac cctgggaaat actactacaa ggtcaaattt 1200 tctagtatct tacagcctga ttgaaggtga ttcagatctt tgctcaatat aaatggattt 1260 tccaagattc tctgggccat ccttgaccca caggtgatct cgctggagta tattaactta 1320 acttcagtgc cagttggttt ggtgccatga gatccataat gaatccagaa cttcaccatt 1380 gcttagatat aagagtccct tggaagaata atgccactga tgatgggggt cagaaggtgt 1440 attaactcaa catagagggc ttttagattt ttcttcaaaa aaatttcgag aaaagtattc 1500 ttttaccctc caaacagtta acagctctta gtttctccaa atatgctctt tgatttactt 1560 atttttagtt aaagatggta atttattgaa caatgaaatc cgtaatatat tgatttaagg 1620 acaaaagtga agttttagaa ttataaaagt acttaaatat tatatatttt ccatttcata 1680 attgttttcc tttctctgtg gctttaaagt ttttgactat tttacaatgt taatcactag 1740 gtaacttgcc atatttctgg ttctatatta agttctatcc tttataatgc tgttattata 1800 aagctggttt ttagcatttg tctgtagcaa tagaaatttt actaagtctc tgttctccca 1860 gtaagttttt tcttttctca gtaagtccct aagaaaacat ttgtttgcca ctcttactat 1920 tcccaatctt ggattgttcg agctgaaaaa aaatttgatg agaaacagga ggatcctttt 1980 ctggtgaata taggttcctg ctttaagaat gtggaaatcc attgctttat ataactaata 2040 tacacacaga ttaattaaaa ttgtgagaaa taattcacac atgacaagta ggtaacatgc 2100 atgagttttg aattttttta aaaacccaac tgtttgacaa aatatagaac ccaaattggt 2160 actttcttag accagtgtaa cctcacacct cagttttgct tttccaaccc tgacttgaaa 2220 ggcatatttg tatcttttta ttagtgatag tgaagctgtg acactaacct tttatacaaa 2280 agagtaaaga aagaaaaact acagcgatta agatgagaac agttctgcag ttgttgaact 2340 agatcacagc attgtaggca gaataaaaaa tgttcatatc tgagaatatt cctttcgcca 2400 tcttttccca aggccagacc tcctggtgga gcacagttaa aagtaacatt ctgggccttt 2460 gtaatcggag ggctgtgtct ccagctggca gcctttgttt taatatataa tgcaggactg 2520 tggaaaacag ttggcataga atattttcac ctaaaaaaga aaaaaaagac atacaaaact 2580 ggattaattg caaaaagaga atacagtaaa ataccatata actggacaaa gctagaagaa 2640 cctttagaag atttgtctga aaacagattt caagagtgag cttttataca ctgctcacta 2700 atttgcttga ttactaccaa ctcttcttaa agttaacacg tttaaataag gtatttctgg 2760 acttcctagc cttttagcaa gcttagagga actagccatt agctagtgat gtaaaaatat 2820 tttggggact gatgccctta aaggttatgc ccttgaaagt tcttaccttt tctctagtga 2880 tattaaggaa cgagtgggta gtgttctcag ggtgaccagc tgccctaaag tgcctgggat 2940 tgagggtttc cctggatgcg ggactttccc tggatacaaa acttttagca gagttttgta 3000 tatatgtgga tttttctgat aagtagcaca tcagaggcct taaccactgc ccaaaagcga 3060 ttctccattg agagtacata tcttgaactt aagaaattca tttgctctga tttttaatct 3120 tgtaaagttt ttgctaaact caaaacaagt cccaggcaca ccagaaggag ctgaccacct 3180 taggtgttct tgtgatttat ccttacttcc ctatgttgtc atagttgctt ctaaactcag 3240 ctgcactatg gctgtcaaca tttctgatac ttattgggat atgtgccatc cagtcattta 3300 gtactttgaa tggaacatga gatttataac acaggtaata gctgaaggta ccagtatggt 3360 ggtgagactc acacttagtg atccagctaa ggtaactgat gttataatgg aacagagaag 3420 aggccaacta gatagctaag ttcttctgaa cctatgtgta tatgtaagta caaatcatgc 3480 gtccttatgg ggttaaactt aatctgaaat ttacattttt catagtaaaa ggaaaccaat 3540 tgttgcagat ttcttttctt gtgaggaaat acatggcctt tgatgctctg gcgtctactg 3600 catttcccag tctgttctgc tcgagaagcc agaatgtgtt gttaacattt ttccgtgaat 3660 gttgtgttaa aatgattaaa tgcatcagcc aatggcaagt gaaggaattg ggtgtcctga 3720 tgcagactga gcagtttctc tcaattgtag cctcatactc ataaggtgct taccagctag 3780 aacattgagc acgtgaggtg agattttttt tctctgatgg cattaacttt gtaatgcaat 3840 atgatggatg cagaccctgt tcttgtttcc ctctggaagt ccttagtggc tgcatccttg 3900 gtgcactgtg atggagatat taaatgtgtt ctttgtgagc tttcgttcta tgattgtcaa 3960 aagtacgatg tggttccttt tttattttta ttaaacaatg agctgaggct ttattacagc 4020 tggttttcaa gttaaaattg ttgaatactg atgtctttct cccacctaca ccaaatattt 4080 tagtctattt aaagtacaaa aaaagttctg cttaagaaaa cattgcttac atgtcctgtg 4140 atttctggtc aatttttata tatatttgtg tgcatcatct gtatgtgctt tcacttttta 4200 ccttgtttgc tcttacctgt gttaacagcc ctgtcaccgt tgaaaggtgg acagttttcc 4260 tagcattaaa agaaagccat ttgagttgtt taccatgtta ctatgggact aatttttaat 4320 tgttttaatt tttatttaaa ctgatctttt tttatatggg attacatttt ggtgttcact 4380 ccctaaatta tatggaaacc aaaaaaagtg attgtatttc acatatggaa aaaaaaaaaa 4440 aaaaaaaaaa aatatgcggc c 4461 140 321 DNA Homo sapien 140 cgaccggcgc tttgtgatgg atccgcccgg gcaggtactc tggtagccca gtttgcaaga 60 gccaggttcc agcagggatg gtagccagcc tgggcacact tttctgtatt gtatttgaac 120 ctcatttcct gatgctcatc cagaagttcc tggctgggtg agtaggtgaa cagttcaagg 180 ctgtgtggat gaaactctgg catctcttta cagtgctgtc cggcagggca gtgtgaggcc 240 actctgtcct cctttgacct ctttcttctt cagcagccaa atggaggctc tctaaaggtg 300 atgattaact tggcataaac a 321 141 1438 DNA Homo sapien 141 gggggacaca gcactgcctg aagcagcatc ttgtaggtca gccagttccc gttgacacgc 60 agaaagacag tactgctggg gttcattttc tgggaaagcc aggcagagcc tgaggaagct 120 tcatgggaag gcagcatgga acttgagctg agccacggag gatggggaag tgggagaagg 180 tcatcgaggt agctggaaag gagagtgttc ccagggagca ttttagaggt gggaacattc 240 aggtgcatag aggtgagagt ggagatgctc cagggagttt gacagcaagc acttggcagt 300 gatacagggg caggggtaca gtctgaaagt gctggactgg ggtactctgg tagccaagtt 360 ttgcaagagc cagggtttcc agcagggatg gtagccagcc tgggcacact tttctgtatt 420 gtatttgaac cccatttcct gatgctcatc cagaagttcc tggctgggtg agtaggtgaa 480 cagttcaagg ctgtgtggat gaaactctgg catctcttta cagtgctgtc cggcagggca 540 gtgtgaggcc actctgtcct cctttgacct ctttcttctt cagcagccaa atggaggctc 600 tctaaaggtg atgattaact tggcataaac atgccaagct ttcctgagcg tttgccctga 660 attgggctgt ctcttgctgc tctgagacag ggagactggc tgtctggctg accagccctt 720 ggggctgagg tctggctgtc aagttgcagg ttccaggcaa ccagcaattc ctggttgtca 780 cctggctcta gagattagag cagcagtgtt gctcactaga actttgtgca gtgatagtgt 840 tctttaatct gcactgtcta gtactgtagc catgggccac ctgtgacttt caagcccttg 900 aaatgtggct accggccagg cacagtggct catgcctgtt atccaggggt gtccaatctt 960 ttggcttccc tgggccacaa tggaagaaga attgtcttgg gccacacata atatacagta 1020 acactaatga tagctgatga gctttaaaaa aaaaatcaca aaaaatatct cataatgttt 1080 taggaaagtt tacgaatttg tgttgggctg catttgaagt ggtcctgggc cttggtctgc 1140 gggtgggaca aagcttgtta taatcccagc attttgggag gtggaggcag gacgatcact 1200 tgggcccagg agtttgagac caggctgggc aatatggcgg atcccatctc cacaaaaatt 1260 gcaaagttac cgggatggtg tcaggcgcta tagtccagct gcttgggaga ctgagcagga 1320 agaatgctta gctgtaggga cagttgcggg cggatacagt atggcccagc caggcaaggt 1380 gacccgtttc aaaaaaacaa cattggccgg cttataggta ataaacacaa acgatgta 1438 142 368 DNA Homo sapien 142 ggccgaggtt agcatttaat ctactggaat aagctggttg ctgtggctta tacctgtagt 60 cccagatact tgggaggctg aggcaggaga atcacttgag accagcctgg gcaatatagt 120 gagacctcac ctctaaaaaa gttttttata aatttacttg tctaaagtgg ggaaagggaa 180 attattctgt tttcttattc ttgcttcaag actatgacag atttgaaaga gaattctaaa 240 gcagatttag agaacctgct tctcttctta tctcctaatc cctaaattgt aatttagctc 300 ttatctgtat tgtgttttgt tttggtaaag ggatgatttt tacattgagt tttaaagtag 360 aataagaa 368 143 540 DNA Homo sapien 143 gccgcccggg caggtactaa gcatattaca ccagtgtgtg tggcttcaaa tagaagactc 60 tctatctcta ggtatcgaaa tggcgaataa gaattgcagc tctgaaaata taatataaac 120 acatttttca gatagcatta tacaaataaa aatacttttg gatactagaa tttggggtta 180 gagctgactt caataagggg aggaaaaaat atgtgcaaag ggaagggagc tcaatttgga 240 ataatatatt tcaaagtatg tggctttgca tttttaaaat gctaaccaaa aaaaatgtga 300 gatagagtga ccccaaggaa ctttttacag ccagcctctg gataccagat atagcattta 360 caacttctga tatgctagac aaattttcca tagttttaat tttcttaaag acatatagtg 420 agtgaacacc aacactggga aggaggtagt gttaatttga tcaaatattg atatttcccc 480 actgattcag aaagtgcttg ctctttctct aggatatctc aaaacccttc caatttttct 540 144 1195 DNA Homo sapien 144 aaagactgca tctatggccc accttctcat aacctcaaac gcagagtact cattctaaga 60 aacacatgca ttcttgcctt aactgaggac tgaaatacca aacccaacca aaaataacag 120 aacttttaag tgccctgatg gaaatgtaca gtatgagtta catccatcca tctatacaca 180 catacagaca ctcatatgta tatacaatat atacatacaa atgataatag ctataccaaa 240 aatgtgcata tttaatacag ttttaaaaag ccagtagatc atggtataat acaatttatt 300 tccactagtg aatggcacaa atggagaaat gcaaaggagg tgtttcaagt acaatgaagt 360 catttttcac aggtgaaaat aaatagtatt attccagtgt ccaacataat gtattctaca 420 aaagtttaaa atgccagaca tttagtactt acagaaatag aaagttacta aagtctgctt 480 tatggtctca aaaagacact catagagttt tcaatttttg aaaagggggt gagaaaaaaa 540 ttggtggaag caggagggag tgtccaggat agtttcttta gtgtactgaa tgtttacctg 600 atgtctaggc aaccaaaaat catgactatg ctaaaatgtt ccatttacca acaaatcctt 660 gacctagagt actaagcata ttacaccagt gtgtgtggct tcaaatacaa gactctctat 720 ctctaggtat tgaaatggcg aataagaatt gcagctctga aaatataata taaacacatt 780 tttcagatag cattatacaa ataaaaatac ttttggatac tagaatttgg ggttagagct 840 gacttcaata aggggaggaa aaaatatgtg caaagggaag ggagctcaat ttggaataat 900 atatttcaaa gtatgtggct ttgcattttt aaaatgctaa ccaaaaaaaa tgtgagatag 960 agtgacccca aggaactttt tacagccagc ctctggatac cagatatagc atttacaact 1020 tctgatatgc tagacaaatt ttccatagtt ttaattttct taaagacata tagtgagtga 1080 acaccaacac tgggaaggag gtagtgttaa tttgatcaaa tattgatatt tccccactga 1140 ttcagaaagt gcttgctctt tctctaggat atctcaaaac ccttccaatt tttct 1195 145 787 DNA Homo sapien misc_feature (344)..(634) a, c, g or t 145 acatttagag aaggttaaaa gaaacagtga gaaatgtaaa cattcaaaat gataattgaa 60 tctctcagtt gtgggaataa ttatcagaga catgcaactg aaaatgtctc acctttcatc 120 tttttttctt aattcataaa gttatcttgt agaatttgat gagaccctcc tagtcattct 180 caactggggc ggtgctgtca ccgaatggtg tttgagagtg ttggggctag ggcacatttt 240 tggttgtcac agcaactggg gtggcatttg ctgcccagtg ccaggaatag taacattatg 300 aatgccagga cagtgtgctc agtaaagtct tccatccaaa aggnnnnnnn nnnnnnnnnn 360 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 420 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 480 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 540 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 600 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnncgaaaa catcccgtaa aaaaaaacac 660 ccccggttcg cttgtccctt cccccttgtg acaaactttt tcaaatccag aaagctgcgg 720 gtaatcatgg gcatagggct gttcctgtgg taaaattgtt ttccggccaa tccccaaaac 780 aaaaaaa 787 146 193 DNA Homo sapien 146 tggtcgcggc gaggtacagg ccgcctactt actgccctgc ctgacccagg attcttagga 60 ggggaaagtg ctatccctgg ggccaggcag ggagccacag ccactcactg cattctcaga 120 attctatcct accaccccaa agattgacct gaaagagact ccccttcctc agtcatgtag 180 aagtccttta cat 193 147 661 DNA Homo sapien 147 tcatgccgag cgcgcgcatg agtgatggat tggtcgcggc cgaggtacag agtcctgtta 60 tttttctctt tggccctatt tggctgctta tattaatgca tcagaacttt atgtataatc 120 atatggattt atacgtaaat taagaaaaaa tgtccatttc attcagttca tatgttctaa 180 acgtattgct gatcattctt aaatgagact ccaggtttac attcttacat aaagtgcagg 240 gatcccgaag ttagccccaa agatcccctt gcctttttca gacttgctca aatgttacct 300 tatcagtggg gcctttcctg accacacttt aaaaacctca acacccaccc atgggccttg 360 tcctccttcc cggcttcatt ttttggcata tacttatcaa atgtgaacat atgatgcatt 420 tgctttattt atcatcgatc ttcactcact ggcatgtaag ctctgtgagt gcaaagattt 480 tcatctagct aatcttccag aacagtgtct ggcacagaga aggagctcta tgaatatgtg 540 ttgaatgaat gactatcttt gccttgtaaa ccccatgcta ttggctctct cttcaggtgg 600 ctgaccactg caccccaggg catgctggaa agacaggagt cccaagccct cccttctgct 660 c 661 148 1897 DNA Homo sapien 148 agttttgcgt tgcgccttgt tgcttgcgtc cgtcgtttgt ttgcctgtgg cttctgccgt 60 ctttttgtgg gctcgccgtt gcccgtgcct gccgctgtca cccttggcgc ccgcctgggt 120 gctggggtcc gcgattgcag tcctttgata gtgttagtga ggggggctgt cgtgcgtgtt 180 gtgtatggtc cgcatggggg agtcattagc atgttgagtt gactgtctcc cggtccgttt 240 aacgtgcgtc tggaaggtac atttttgtaa atcaagtagt tggaactaaa tccaacactg 300 ataattgcca tttcaaacac tgatctgaaa agtgaattag aagctgtaca atatcatcat 360 tagaaattct gcatatggct aataaatatt ccttttaaaa ttaatagagt ctaaagtctt 420 ccacatgatc tttacagata gagtgggaca ctatagaatt ctgattatat gatttagatt 480 ttagggatgt tttaacattt tcaaaccact agaaggacat tgggaacaga aagtaataga 540 gccaacgtca cgtggtaatg atcaatagtc cagttctacg aggagaacaa ttttaagctc 600 ttcactgagg ccaattctgc tgtattctaa ttccttttag gttcttggtg gtagagtaat 660 gagctatgac catctctgga atactggtga ggaaaatggc agcagtaaag aaatgaggaa 720 aatattacct aattaatgat aaagttaggt ccagtacaga gtcctgttat ttttctcttt 780 ggccctattt ggctgctttt attaatgcat cagaacttta tgtataatca tatggattta 840 tacgtaaatt aagaaaaaat gtccatttca ttcagttcat atgttctaaa cgtattgctg 900 atcattctta aatgagactc caggtttaca ttcttacata aagtgcaggg atcccgaagt 960 tagccccaaa gatccccttg cctttttcag acttgctcaa atgttacctt atcagtgggg 1020 cctttcctga ccacacttta aaaacctcaa cacccaccca tgggccttgt cctccttccc 1080 ggcttcattt tttggcatat acttatcaaa tgtgaacata tgatgcattt gctttattta 1140 tcatcgatct tcactcactg gcatgtaagc tctgtgagtg caaagatttt catctagcta 1200 tcttccagaa cagtgtctgg cacagagaag gagctctatg aatatgtgtt gaatgaatga 1260 ctatctttgc cttgtaaacc ccatgctatt ggctctctct tcaggtggct gaccactgca 1320 ccccagggca tgctggaaag gacaggagtc ccaagccctc ccttctgctc tactccaagc 1380 ttttcttctt gggtgcattg actcaagtca ggtagtactt ctctatgtct gagcacagac 1440 gggctgtgtt catgtatttg tacatatgtg tgaatagaca gagaaactag tagcatgggt 1500 atgtggggga atccatcttt tagggagaga tttatctact gtttttgtgt ttagtctcac 1560 ctcagaccag gttaagctgg ccagggctca tagttttcaa agagcaacag aaaaaatctg 1620 tttagcttac attctaagca tgttctcttt atctttcctg aaagctatcc acttttaatt 1680 tcatctcata ctacagagaa aatattattt gaaactgata gctttccaga aggttactga 1740 aatcacttat ttttcagtgt cttcactggc accattcata gtagctaaca ttagccactt 1800 tccgtgggcc tggtgctgtg ttaaagtgct ttacatatat tatttctttt aatccgcaca 1860 atgatccttt caagtaggta ctgttattat tcccaat 1897 149 254 DNA Homo sapien 149 ccgaggtacc catctagctt ctggggctcc actgacagct gaggacagtc cacacccgac 60 ctggacccca ccccaccctg ggtctgtcca tctcagtccc ggcctgagcc tctgggccaa 120 agccacctct tctgagcagg caggcagagc gaaagactgg gagcagcaga caggggcaga 180 gcacggccca tgagcccacc ctccacttcc cagattggtc agagttacat ggtcaccttc 240 cctgcacctg cacc 254 150 1993 DNA Homo sapien misc_feature (1822)..(1822) a, c, g or t 150 aaggatcctt aattaaatta atcccccccc cccggggcgg cccagcggat cgtgccgcgg 60 cggccgagcg cagctacagg agggtgtcca gaagccacaa gccatggctg tggggaacat 120 caacgagctg cccgagaaca tcctgctgga gctgttcacg cacgtgcccg cccgccagct 180 gctgctgaac tgccgcctgg tctgcagcct ctggcgggac ctcatcgacc tcgtgaccct 240 ctggaaacgc aagtgcctgc gagagggctt catcactgag gactgggacc agcccgtggc 300 cgactggaag atcttctact tcttacggag cctgcacagg aacctcctgc acaacccgtg 360 cgctgaagag gggttcgagt tctggagcct ggatgtgaat ggaggcgatg agtggaaggt 420 ggaggatctc tctcgagacc agaggaagga attccccaat gaccaggttc gcagccaggc 480 cagattgcgg gtccaagtac cagctgtgcg ttcagctcct gtcgtccgcg cacgcgcctc 540 tggggacctt ccagccagac ccggcgacca tccagcagaa gagcgatgcc aagtggaggg 600 aggtctccca cacattctcc aactacccgc ccggcgtccg ctacatctgg tttcagcacg 660 gcggcgtgga cactcattac tgggccggct ggtacggccc gagggtcacc aacagcagca 720 tcaccatcgg gcccccgctg ccctgacacc ccctgagccc ccatctgctg aaccctgact 780 ggtaaacaac tgctgtcaga aaagggctgg gcttgggaag gggaggtgga ggccaggtgt 840 ccccagacct ctaacccttg cccctagcag cctcttcttt gtggagcctc tcagtgtggg 900 cagccctcgc atgctggggt cgggccagct ctccccgaaa ggtcttgacc tgaatgatgg 960 ccggggaagc ctgcgtgtgc ccctttcaga gacggagcac ctgagatgtg ggaggtgcag 1020 catgttcccc tgggcccctc agaaagtcga gcttggaggc cagcctggat ctgtctctcc 1080 cttcccctcc tgggaccatt ctacctgtgt tctttgaccc tcggagcagg gacaggcaag 1140 acaactggca agcttgcagc tgccctgatg gtgcaggtgc agggaggtga ccatgtaact 1200 ctgaccaatc tgggaagtgg agggtgggct catgggccgt gctctgcccc tgtctgctgc 1260 tcccagtctt tcgctctgcc tgcctgctca gaagaggtgg ctttggccca gaggctcagg 1320 ccgggactga gatggacaga cccagggtgg ggtggggtcc aggtcgggtg tggactgtcc 1380 tcactgtcag tggagcccca gaagctagat gggtaccagg tggggttagg ttcccagagg 1440 actgagggaa tcctgtacag gatgtcccag ggtagatggg gagcaggatt gggacctgct 1500 ctgacagctg gacacatgag ccctggatga gtatggtagg gggtttgaag aatcccctgt 1560 ccacctccca aatccaggcc cggccccctc tggcttggag agcattccaa gcccccaccc 1620 cacccctaga actgccattc ccaagacctc tgtctcccag ccaaccaccc ttggaacttg 1680 cctcttgtcc tgctggaaag atagcagtgt tctcctgact tcgccctact gcatgcagcc 1740 aaataaaagg tgtgcccagt ctaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 1800 aaaaaaaaaa aaaaaaaaaa anaaaaaaaa aaaacaaaac tattgcttgt gtttccgttt 1860 ggattggctt tgcgtatcta ctttcagtgc tttcgtcatt tccttcttcc tagctgctta 1920 tcatgcgata ggctacactg tgctcctttc tcaattttac ccagttctaa tgggaatggt 1980 gtgtttagat ttt 1993 151 170 DNA Homo sapien 151 gcgtggcgcg gccgaggtac atactcatat ttataaggac ttcctcacta ggagagattc 60 ctgggttcta cagaataaaa ttcttggcta cttgtcttat agctctgaac agacttattt 120 tcccagagag tatgtttatt atgtaatagc gagttgcctg accccccaaa 170 152 1394 DNA Homo sapien 152 taggtctgta tagaatacga ctgaaagatt ttgactgttg atttcctttg aagagattct 60 cctgttctcc tcttcagagg aaagagagag gagagaggga gagaggagag aaaagagaga 120 agagagggtg acttttcatt atatgccttt gtaatattta atctcctccc ttttctcacc 180 cccttgagca tgtatgcttt tcaacaatta aaaagattaa aaagctctta aatagataag 240 aatttcttag agcaactagt aagtacacta actgccaatt gttttgaaat gtagacattc 300 tgaaaaatca aaatgattgt gccgaatgta ttttaaaagg ctaaaatatt atagcatttc 360 aaagtacata ctcatattta taaggacttc ctcactagga agattcctgg gttctacaga 420 ataaaattct tggctacttg tcttatagct ctgaacagac ttattttccc agagagtatg 480 tttattatgt aatagcgagt tgcctgaccc cccaaaaagc tgtgttctat catattaaaa 540 taaggcaaaa tgattacttt cagattaaga aattgtggga ctctagatct tgttatatag 600 tgaagttctt taaaaaactg aggtcttggt tctgaataat agtgggttta cattaattta 660 tttagaattg tcattggggg tatctctgac ctatttttat aaaataatct caatttttaa 720 aataggagta aaatgctcat tggcataagc cagtaataat aatttagtat ttttccaagt 780 atttatagtc aatgtgttgc catgaacttt tttaagggat gtttttaatt ttagaagtgc 840 tttaaaaagc aatatggcat ctggctctgt agaagtagaa aacatggtaa cttcaatgtg 900 atatatttgc ttttttcccc tcttaggtct ttggggtaaa aaaaatccaa agtttactca 960 attttatttc tacatatatt acctacaaat tatagaggtg agacctgctt gctgcctgtt 1020 catacctgtc agtgatacta atacctcccg tctgtacagt gtttcatagt ttccaaaggg 1080 ttctcgcatg gttcctcact tgagcctggt gaggaaatac ctgtaaacat gggtagaagt 1140 tttagtccct tgtaaaactc tggtataata tcaaaaccag gaaattgttc acagattcta 1200 aggattgggg aaaagagaaa aataaacaaa ttgctcagga gtagaattga aaaaaagaaa 1260 aaaaaaaaaa aaaatttggg ggcgggccga aatttaaaca gttggggggg ccaggtggaa 1320 tggaagggca ggaaacggga gatggtgttc caaaaaagcg gggcgggtga aaaagggcgg 1380 gggggtacga gggt 1394 153 368 DNA Homo sapien 153 gcactgagaa aggatatgga caagtcagtc agcattcaca attaagagaa aaacatctgt 60 gctttggaaa atgttcttca aggatagaga attgtgccct atgtccacca aatttgcatg 120 agatctttat aagattagac agccagtgga taaggcccct tatctttctt catggatggc 180 tgaggaaatt ctccgccttc cctgacatca gctgcataac tgtatttctg cctcgtggaa 240 ataaagtaga tgatcaggca cttgcggttt gttcttaata caagaaagac aatttgattt 300 ttaaaagttt tgatttgtag aataatgtaa gacaatatgt ttctttctac tttggttttt 360 ccattcaa 368 154 864 DNA Homo sapien 154 ttgatatatt gcattcttga gcattaggct tctaggtgat ttgttaaact catagcaggt 60 tttagtacac agtgctgttt atgacagaaa aaaattttat cctacctctg aaataattgt 120 actttctgtg attcagataa aaactttata gaaactccct aatgaaaata ttgaagcatt 180 aaccagaaaa tgagtcagct ttttgtttcc aaaatgatgc aacaggaaaa cctttaacta 240 cttataatcc cgtatagtca ccatcaccac aaagtattga aaatctgttt tctcttttac 300 taagtgtctg cacggtcact tatgtatacc caaagccaga aagatatttt tatctcaggg 360 aaattccaga aatggaaaca tttttgtgta atattgattc atttctgtct caccaaagat 420 gtgttttcca cgtagcaaag aacatcagcc ccacgttata gggaacaagc gagtcccaaa 480 tcgtaccatc tgctgagcac tgagaaagga tatggacaag tcagtcagca ttcacaatta 540 agagaaaaac atctgtgctt tggaaaatgt tcttcaagga tagagaattg tgccctatgt 600 ccaccaaatt tgcatgagat ctttataaga ttagacagcc agtggataag gccccttatc 660 tttcttcatg gatggctgag gaaattctcc gccttccctg acatcagctg cataactgta 720 tttctgcctc gtggaaataa agtagatgat caggcacttg cggtttgttc ttaatacaag 780 aaagacaatt tgatttttaa aagttttgat ttgtagaata atgtaagaca atatgtttct 840 ttctactttg gtttttccat tcaa 864 155 179 DNA Homo sapien 155 gcggcgcggt gttatggagt agcgtggttc gcggccgagg tacatgtttt taaaaaatga 60 ctacatgttt cacctggtcc tatttttgct atttggacca tacttttaag atgaattgat 120 cttacataca tgttaagtct gatttatctc cccacatttt taaacactaa atgaagctt 179 156 1849 DNA Homo sapien 156 gcttgatacg ctcctaagga atttgccctc gagcaagcaa ttcggcacga ggctcgaacc 60 cctgacctca agtgatcagc ccgcctcagc ttcccagagt gctgggatta caggtgtgat 120 ccactgcacc cggccggcat tatgattttg tgtactcttg aaatggttat ctttgtggat 180 gatttttttt ttttaagctg aaacttacct catgaataac ttgattaaag tagtaggtga 240 ttaaaatttc aatagaatca aatgagacaa aaattttaaa ctgactcatt tgagtttcaa 300 ctttacagtc attgaccata aagcacacta aaaatgtaag ttatttttaa atacatctga 360 aataaaaata cttactaaaa aggaagaagc cgaagatgta tatttagacc agcacacaat 420 tttgatttca attagcctta ttctaatatt tagcttttag atctttcata cacattttca 480 cgtactttgc aattgagacc agaaagactt gtaggtcttt ctgcagaatg agtgggtcct 540 tgcaaagtga gtgggaaact tactcctaga tcagaaatgt ttgcctctct gagtaaaatg 600 tttctttcag atgagccata gagggggcac cttttactca acttttcttt gttttgaaac 660 tttgtttccc atactgtttt cagccttttg tttataatta gaaattgtga gaagcttcat 720 ttagtgttta aaaatgtggg gagataaatc agacttaaca tgtatgtaag atcaattcac 780 ttaaaagtat ggtccaaata gcaaaaatag gaccaggtga aacatgtagt cattttttaa 840 aaacatgtac ttggtctttt gtgtgtgtct gttttattcc attagaataa atgtgtcctt 900 gatgtaaatg caaagcattt cttcctgatt aaattgtaga tgtagacttt acaatataat 960 tcaataataa aaagtaatta acctctaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaacac 1020 ttgttgggcg cggcgcgggc ccggagaaaa gtttttaaaa cccttcgtat ggcgcgagga 1080 ggggccccag gtaggggaac ggaacacagg ggccacggcg gtgtagcaag agggaaaacc 1140 cggtggcgaa gaaaaagggc gtggattctc acccaataaa aagcgcgccg ggggggaacc 1200 ggaaggcgtt tgggaaacaa gactctcaga aagagggaga ggcgtcagcg gaggcgcaca 1260 ataaaggggg gactcctcac aacaccgggg aggagctccc gaagaggaga cgccccgaaa 1320 tagacaacaa ttacagcccc cgggcgcgcc gggggcagat accagaagac gaagcacgag 1380 acgaagtagc acaagaagaa aggacagaca gaagcgagac gagaggacag aagggaggag 1440 agagaggcgg aggcgagggc gaaaacaagg ggacgacagc aacgagaaga gaaagaaaaa 1500 cacgacggag gaacggggcg gaaaaaggac gagaaagccg agagcaggcg ggcgggggca 1560 cacgggggaa acgaagagca aggaaagaag acaacaggag aggaggggag ggaagcgagc 1620 gaagagcgta gagacgccga gcaacaagaa gctagagaca gcagtagaca cggacagaca 1680 gacacggtga tggtagccgg ggcgggggga catcttgggc gcgaatgctt cgccggggaa 1740 cagacagcgc agggcgagca gagcgaggaa acgcagggaa cgacgcgaca gacaggaggt 1800 cagaagaagg gaagatgagt gcagcgggaa gaccaacgga gaaggagag 1849 157 903 DNA Homo sapien misc_feature (139)..(139) a, c, g or t 157 ttgtttgttt tttttctttt tttacatttt tttttttttg tggacgaaac attcacacag 60 aaacagctag gaccagatta cgccagcttc atgagacctc tcctatctgg gcacgttgag 120 ttggctgact ctgggagcnc aggctgttgc ttcccagtct ggtggtgaat cctccatggt 180 ctggttgagt ccttttcaac tagtttttgt gttgtttttt gaacctcaag tcactgactc 240 cttcagcagt ggtttaagga agtatcttaa tttttaaatc acatgttgac catgcagcca 300 attgttggcc cgtagagtga acaaaaccag accacaagat tgagggcttg gagctggaga 360 aagggaaaag aaaaagcagg ctgtgactct ctggggaaag aactgaaaga tgacactagg 420 aattctcaaa gcgagaggaa aaggaaaggc cctttttcgg aaatgacctc tgataaacac 480 accctccagg gttacacctg ccactgtgtc ttccacggac agacaagctg cactttagca 540 gtcctgaata cctagagact tccttaacag agagtgggga atctcgtcat cttgcatggg 600 gatgggagct cgaagggaga acctcagcct tccagaaggt tatataaaac cagttgagaa 660 tttccctaag aatggagcag tggacaaaca attgttattg taatccaaat acatgagtct 720 acctacataa tggagaaatg ctaacttaca gaaagcgtca ggcttggtgt tctcgaactg 780 gttttaattt ccttttataa aattacagcg aattatacaa ttacattgat taattgtaat 840 cagttctgag tctagataac aaaacacaac acacacaaac aaacaaacaa cctctcctca 900 aac 903 158 368 DNA Homo sapien 158 gcggcgcccg ggcaggtaca gtggcaacag cattagacta agtggaacat cccagcaggc 60 tgctttagaa tccgctcatt tgactagata cgatgtaatt ggctgtcttt aaaaaacgcg 120 cacacacaca caatctgata ggcatatctc atgcccattc aatatggaat gttcttcgct 180 tgctgaattt aagcctgtat tttaaggttt gtggttcctc ggccacaatg ggtgatgtca 240 ctgatagaac gaagctgagt ttccaagggt tggggctgtg caagagtaaa cactagagct 300 tgagttgtta tccagctggc aagcacggaa gtctttgaag aatgtaatgt aaaaagggaa 360 aagaatgt 368 159 1548 DNA Homo sapien 159 gtcgcggccg aggtacatag acacaggaca attaataatt tggaaaacaa aagacttact 60 tatctccata tctgctaatt gtctcccaat ctccttaaaa tgcacttatt agcaatcatt 120 tttcaccacc catttaccca aacaacagga caaagactca atttcctatt ttatacaaaa 180 catgataagt cagccaagta ggttctggac cggacaacaa gggagatatt aaattatagt 240 atttatataa aagtggccca ttcgtgtgat acaaaacgtc tcattatgtg gaccaagaaa 300 catataaaat atatcaatat ataagttgga aaaaataaca aaaaagcaca cacattaata 360 aataatcata ttacacacac ccacatctat attctcttat atacacgcac acacaactgt 420 gtgtcttaac aacaaactct ccattttata aaatatctca ctgtatctct ttataaccac 480 aagaaagatg gaaacacaat aaacaccaaa aacaaagaca cacagaaatc atttgtgcgc 540 ctatatataa taatcacact cagtatattt aaccaacact tcccccccca tatcatctaa 600 tttatgtagt actctataat gtatcatcta gtatattatg tagaaaagtg gcgccccata 660 tattatacag ccgggcgccc acgtgtatat caaacaacag ctgttgtcgt tctgcccggg 720 gagcacaaaa ggtgtataac aacaaatgat tatattcttc acccgaggaa gaagataatg 780 agaagggagt aataataacc agcgaagaag gggcgggggg acataataac accgctaatc 840 aacaccaaag aacgcgggcc aaacgaaaca acaacacaaa cgagatgttg tgccacacct 900 cagtaacacc tacatgtcag cgcgcagcga caaaacaagg gcatgaccag aagaaacctg 960 aaaaaactgc ggcaaaggga accacaccac cgacacacac accccaatga ggaaagagaa 1020 taaaaaacac atagttgagg acaccaaaaa aaggacagga ggaaaaacac actgtggggt 1080 gtgcaaaaca cacgttgtcg taacaacacc gcaggagatc acaaaagaaa acaccccaag 1140 acacaacaaa atataagcga acaccacaac aacacaacaa cgaaacaaaa caagaaaaaa 1200 caaaacacac aaccgaaaca aacaaccaaa acgaccacca gaagcacaca acacgagacc 1260 aggacaacac cagacgcaga cagacacgag atgatgcaca cgcgcatcgg ccgagccagc 1320 aaacggcacg ccaacaagca agacggccag cggagaacac gagcatgtcg aagtaggaca 1380 gcccgccaag acgacaaaaa accgaggaga agagaggaag aacacagaaa ccgcgaggaa 1440 aggacaacgc aggaggcgag ataacggcgg acaagcgcaa gaagggagca gagaagacag 1500 aaggcaagac acgaaacaaa aacacacaac gaacaaacac gcgagagg 1548 160 552 DNA Homo sapien 160 agaagactga ctcatatagg gcgatggtca ctagatcatg ccgagcggcg ccattgtgat 60 ggatctagct ttggctactg ccggtagtgg acaatatggc acatggaaat taaaaagtcc 120 ataaacgtgc cctcctaaca cgagaataag aaaggtggct gaagtagata atttcagtga 180 cggaggggat gaaatatttt ttggttaatt gatgtaatga tgactcacta tgccttattt 240 cctattttta aaaacacaga atgagcaagt cattcctgaa caaaaattta ctgtgtgtat 300 aacatacacc tcaaaatgaa ttttaaggga acatattact aatcaaataa cacagtttat 360 gctttttcaa tttccacaaa ttgttaatta tgatacttaa gggaaccctt acaatatata 420 acaagtcatt tcaatattat tcatcatcct taacttctga aagtttggtt tatgttatct 480 tatctagaaa gaaaactact tacaaatctc attttcccac aaaattaatt caacatccaa 540 ccttaaaaat aa 552 161 3937 DNA Homo sapien 161 tgtagctggg attacaggca tacaccacca cacccagcta tttttttgta tttttgttag 60 agacaggttt ctccatgttg gtcaggctgg tctcgaactc ccgacctcag gtgatccgcc 120 cacctcggcc tcccaaagtg atgattttat ttttattttt aattgtatta atctgcatct 180 agataatgac tttgtgaagg gtgtgtgttg tgtgcaaaac ttaaggtatt ggttgagagt 240 taaatacatt atttttataa tatgttgggt atagtctagt tactaatgat tttttttaag 300 tacttttata aaaagttcat ttttaaaatt gtttgttttt aaaagccaat atacgttgca 360 gaattaggaa cagtatttat atttatttac acaagacatt gtgccatagc atcctagtaa 420 aacaccttca tgaatgagta atgttatctc ccagaattac attaaaatta tttctaaaaa 480 gtagcaaagt cattaccttt tgcttttaat gacccacacc tcaccagctc ctggtctttt 540 cttcactgtt gcccttattt tgaggcaatt tttcttaaaa tatgactttt atgcaccaca 600 tttagtagag gcagtgacat cagtgatctc agtacccatc agctgtcccc ctcctctgcc 660 cttcttcatc tcttctacct tgtgaccatt tcccttaccg gttcatgttc tcctttatct 720 ctgcttttct ttcttagcca ggatacttcc ctcacaactc tcactcccaa attcttttag 780 atatacattt ttctggatat tggctgctga aatctgaagc tctggtaaag ttcctagtat 840 cagagatcaa tcctggagga ggcctagttc actattagat tacaaagact cctcacaaag 900 taaaggaaaa tcaccttcaa aaccacaacc ctttatgttg tcaagtctaa tatgagtgtt 960 tttacgaagt atttctttct acccattgtt caagaatgta aatgtaaaaa aaaatacaag 1020 agagttgggt agatatgcat gcttgaggaa acttgctttt actgttttcc tacttgtatc 1080 cccagttcag ttgaatttac aaggacctac aagatggtca tgtttgtctt ggtatgtgct 1140 accccaattt tagtgtttct ttctttattt taaatcagta attattcagt tgattgttta 1200 tactatataa tgaagtaaca aaaacatttt ggtttgtatg ttttaagtaa cagttgtgca 1260 aattcctctt gtttgttagg tgctcccttt gaatattttg tgaactgtgt cagagggaga 1320 ggggtggtgg ctaggaagag ggtcagaaag aagctagagg gaggtcagga gaagggtaac 1380 agggaggatg caaagcagac atctaccctg gtcaccccag gatcaggata tctgtccttg 1440 tttcatgttg aattcaaaaa ttggatctca cttaggcttt gaaggtgaca gccatctctg 1500 atagctgagc ataagtaaag aaaggtggag tgccgatgca gaaaggaaaa tattcagctt 1560 tcctctctta gatcgcactt tgaagatggc cttttggaga caatctgaca ggttaaaaca 1620 ggaactgttg gaattattct agctgtaact acctattggc tatgtgttga ttgatcctag 1680 aaagaaaaaa taatttttca ttttagatct tgattgaatt taagatgtat ttatatgcct 1740 acaaaaggtc tgtcttgtaa ctgttgtata aaataaacct aatctatggt ttcattttta 1800 atctaaaaaa agttgtgcct taacaatagg gcattgtatg ttaataaggg aaaacaacct 1860 ttttagtaga tgggggaaaa taggaacttt ttgccattaa aacttaagtt cttttgatgt 1920 ttttaatatt atagttgggg gagattcatt aaaattaaat tgaaataaaa ttatttttgc 1980 ataacctagc atttacaact aaagtatgtt ttttataaga actggcatct tgatgtatat 2040 aggtctgaaa taatatttca tcttttgatt tttaatttta ataatattag accaggatag 2100 atcacagttt tacaaatctt agttttaaat aaattatttc agtgtgctgt tagtcctcta 2160 cagtcatttt ggtttaaaaa gtgactattt atttatggta gcatatcaat aatttattaa 2220 tgttaaaaaa tactgtgtat gacattacaa accagaacag ttcctggggg agaggattct 2280 aattgattgg cagttctgag agggcaagaa gaatggaact ttatacttca aaaggaggtt 2340 ttggttttac caggtactgc ttatgtaaat cgtttatttt tatttcatca aagcctggca 2400 agtatatgca ttccaattta ccattggcaa agctttattt atttttaagg ttggatgttg 2460 aattaatttt gtgggaaaat gagatttgta agtagttttc tttctagata agataacata 2520 aaccaaactt tcagaagtta aggatgatga ataatattga aatgacttgt tatatattgt 2580 aagggttccc ttaagtatca taattaacaa tttgtggaaa ttgaaaaagc ataaactgtg 2640 ttatttgatt agtaatatgt tcccttaaaa ttcattttga ggtgtatgtt atacacacag 2700 taaatttttg ttcaggaatg acttgctcat tctgtgtttt taaaaatagg aaataaggca 2760 tagtgagtca tcattacatc aattaaccaa aaaatatttc atcccctccg tcactgaaat 2820 tatctatttc agccaccttt cttattctcg tgttaggagg gcacgtttat ggacttttta 2880 atttccatgt gccatattgt ccactaccgg cagtagccaa agctagctgt ttcagtccca 2940 cagaagagac agtgctctgc catgatgaca gggcactgct agggctggtt tttcttgttt 3000 ttcccttttg gcagtgtgga cttcaggaac tagatgtata tgcacaaggg attgagttta 3060 cactaaaact aggaaatgga gttttcaatc tatgttcttg cctcttcata cttttattta 3120 ttttttgtca tcctgcctta tactgggcta acaatgagat aaaataaaaa tacctttgaa 3180 tactcttttc cctttcatgc atttaaagcc atggaggaac tagaccatta gctgttgccg 3240 tcacatgctt agacaccagt ttacttagcg tgttatgacc ttcctcaccc atactaccaa 3300 atttaaatgg gtcccgactt caccctctgg aaggaagtaa actcttctct ccccatggtt 3360 tcagagcagt ttttacctgc aagcaccatc tctgtatgtg ctcttactag attatacagt 3420 tcttgagagg gattgcatct tggtgttttt gtatttccac ctcaccccca gcacatagcc 3480 cagtctcttg cacaaattaa gtacttaatg tgtgttgagc taaattgaat aaaggattat 3540 tagcattagc atattttgtg ccttggttgt ataagctggt tgtttgtttt gttacctttg 3600 caaatattta tgattatcac ccccccacat actaaattgt ttttaaaagt tttgcctttc 3660 cttcagatac taccccaggc aatttgctgt agataatgtg attgcttcca atgacataat 3720 tatcccaaac tctctgcccc ggatatactt tgccaaacga aatttgaatt ctctgaataa 3780 attggtcatg tctaaaaaaa aaaaaaaaaa aaaattgggg gcgggcgaaa aattttaaac 3840 atgtgggggg gggcaatgaa agaaggcagg tccaagacgg ggaagggggt cacaaaaagc 3900 ggggggttga aaaggggggg tggtataggt aacgggg 3937 162 852 DNA Homo sapien 162 cggccgcccg ggcaggtacc accatgccca gctaattttt atatttttag tagagatggg 60 gttttgccat attggccagg ctggtctcaa actcctgaac tcaagtgata acacccacct 120 tggcctccca aagtgctggg attacaggtg tgagccacca cactgggcca atgcttaata 180 ttttaatgta tctcaacaat aaaaccaaga agaaacaaag ccttttgact tgttagaatg 240 tattaagtag tattttaaag aaactttata gttgtgacat tgaaagactg ttggggtggg 300 gggaggaaaa tttttacttt ccatcttaat gtaaccttat gctattctgt atttttactg 360 tatattgctt ttacaataaa tataaaatga aaatgtttat gttgacaaaa agaacaaaaa 420 acaacaaaca acaaaaaaca aaaggctggg ggtgtcacac ctgtgggcca aaagctggtt 480 tccctggggg tggacatttg gttttatccc ggccccacaa ttccccaccc aaatattacc 540 gggagacaac gggaagaacg acacaacaca caaaaagaca caacacacaa aaccaccaca 600 cagcaacgcc cgctcatcgg aggcagcgca caagacgaga gcagaaggaa aagggacaac 660 aaaaaaaagc aagtagcacg atcacaacac agagccacga caagaagaga aggacaatga 720 cgaaaacgag cagcagcaca agacacagac aagacaaaag caagaaagac agaacacgac 780 agaagacaac aagagacgaa acaaccaaaa agccacacaa aaaagcgagc gaaaacaaga 840 accaactaac ac 852 163 685 DNA Homo sapien 163 caccgatgat taaccagtac agacgctgtt ccactagatc atggcgagcg gttcgcagtg 60 ttatagtagt gcgcggctga catacttcat ctgcttttta ttgttgttgt tgtgtttttt 120 aaccaaaatg gcatttgttt ggctgtcatt gtcgagtata tatttattgt gttttacaaa 180 catgagtata tatgtatgta tatgtataaa ccaaacttat atatatagaa gtcaagggca 240 tgtatactag atattttaaa gagttattta tcaagggaaa aagatgtgtg ttataaagta 300 aacagagtct atattttcta tataatgtag atagtcaaac atagcttata aattatagga 360 ggttttggtt ttctttttta ttattaaagg aaaaaaagaa gaaaaaaaaa gacaatgaat 420 gcaactgttc ttagtgtttt taaggccaaa ctactgtgga agctgggagg cggccctccc 480 tgcgggcctc cagcagccct gtgcctgccg ctaggagctc cagagctgat gcccgttgtg 540 atctctgcga tgctcgatgc tcggagccag cggtcagcat cactcagcca gctggcctgt 600 gccgctctga cgtggcttcc agctgttctc cgcaatttgc attggtggga taaaggaatg 660 aaaaggataa ataaagattt aaaag 685 164 2396 DNA Homo sapien 164 cggccactga attcccttgc ggccgcagaa tttttttttt ttttttttgt attttctttt 60 aaatctttat ttatcctttt cattccttta tcccaccaat gcaaattgcg gagaacagct 120 ggaagccacg tcagagcggc acaggccagc tggctgagtg atgctgaccg ctggctccga 180 gcatcgagca tcgcagagat cacaacgggc atcagctctg gagctcctag cggcaggcac 240 agggctgctg gaggcccgca gggagggccg cctcccagct tccacagtag tttggcctta 300 aaaacactaa gaacagttgc attcattgtc tttttttttc ttcttttttt cctttaataa 360 taaaaaagaa aaccaaaacc tcctataatt tataagctat gtttgactat ctacattata 420 tagaaaatat agactctgtt tactttataa cacacatctt tttcccttga taaataactc 480 tttaaaatat ctagtataca tgccttgact tcttatatat ataagtttgg ttttatacat 540 atacatacat atatactcat gtttgtaaaa cacaataaat atatactcga caatgacagc 600 caaacaaatg ccattttggt taaaaaacac aacaacaaca ataaaaagca gatgaagtac 660 tataaaagca ccaggcagca gacagaaagc cacatttgct agaaacttct ccctcccctg 720 ggcaaggcac agggcagaat actaaatacg tccaggtgcc tgaaagagaa ggaaggcagc 780 aaaggaatgg gtcagatcac aagcttttgt tttgtttctt agcctgggat tagaccaaga 840 atcacaagta agtcattgcg tttataagga aaaaccaagg ggctcattca acagcttagc 900 ccttgtggtg gctgcagggg acagtagaga cctggaaggg gaaggagaga gacagtgacc 960 tggtgacaac tccatgacta ttgtctagcc cctgcctaca tctgcccagg caagcttttg 1020 attgccacac taagcatcaa gccattgcat ataatatgtt cttttcatga ctctattcac 1080 tgctggtgta aacagaaagg agtattcagt agtgcaacac tttgggaggc tgaatgagag 1140 ccacagtttc ggtggccccc tcaagggctc cagcaaatgg ggactgtgac gtgggggaga 1200 aaaaggccag tgggccattg ccttccactc ctgagacagt accggcttca cctccagatg 1260 ccactgggaa cactgagccc atcacctttt aaagaagcgc aggaggtctt gactcttcct 1320 atgagaagtc ccagaagccc cagtcagtct gggtgggggg tcccctgaaa ctcagagcac 1380 gctccagctg ctggctcctg tgcctggcgg ggagaaggtg gagaggcggg catgcctgcc 1440 gctgagaaag acataataac gctccagctg cacacccctt ttcttccacg gccctcctct 1500 ttctccccaa aaggaaacta aaatgtgggg ttctgatcat tgatttttaa acaagctccc 1560 caatgtcatg gcctctgctc tgtaaactcc aaggctctga tggccaaaaa cgtaggcggt 1620 ggtggagcag taggcggtgt caaggctaga tttgtattaa tatctaggag tggggtgggg 1680 atgcaggtgg agggtgagcc aagtagacca agcctcagga aatcccagag gtgaagattt 1740 gatgcacatc ccccatcctt gccaaataaa atacaagtta gaggtcattg ttcacattac 1800 agtcacaatg ggacatttta aacagctcgt tttctgagta cattcaagac ataattgaat 1860 ttattttaaa aaatggattt cccggctggg cacggtggat cacgcctgtc atcccagcac 1920 tttgggaggt caaggaagcc ccttcttcac aggacatcct ggtgttcctc actgggcagg 1980 aggagatcga agccatgagc aagacgtgcc gagacattgc aaagcacctc ccagacggct 2040 gccctgcgat gctggtcctt cctctgtacg cctccctgcc ctatgcacag cagctccgag 2100 tcttccaagg ggccccaaag ggctatcgca aagtgatcat ttcaaccaac atcgctgaaa 2160 cctccataac cattacagga ataaaatatg tagttgacac gggcatggtt aaagcaaaga 2220 agtataaccc tgacagtggt cttgaggtgt tagcagtgca gcgggtatcg aagacgcagg 2280 cttggcagcg cacagggagg gctggcagag aggacagtgg catctgctac cggctctaca 2340 cggaggacga gtttgagaag tttgataaga tgaccgtgcc agagatccag aggtag 2396 165 11 PRT Homo sapien 165 Met Arg Tyr Leu Pro Gly Leu Ser Ala Arg Ile 1 5 10 166 45 PRT Homo sapien 166 Met Ser Ile Pro Arg Ala Glu Ile Ser Leu Leu Glu Ser Phe Gln Leu 1 5 10 15 Thr Ser Thr Val Ala Thr Ser Glu Ser His Lys Ser Asn Gly Ser Cys 20 25 30 Arg Lys Pro His Leu Leu His Cys Pro Arg Ile Asn Gln 35 40 45 167 37 PRT Homo sapien 167 Met Ile Leu Gly Ser Asp Asn Gly Ile Arg Arg Ile Lys Tyr Leu Gly 1 5 10 15 Ile Gln Tyr Tyr Ala Cys Ser Phe Phe Gln Ile Val His Gly Gly Gly 20 25 30 Gly Cys Val Ser Gly 35 168 82 PRT Homo sapien 168 Ser Leu Ser Val Ala Gln Ala Arg Val Gln Trp Arg Asp Pro Gly Ser 1 5 10 15 Leu Gln Pro Leu Pro Pro Gly Phe Lys Arg Phe Leu Ser Leu Ser Leu 20 25 30 Pro Ser Ser Ala Gly Tyr Arg Arg Ala Pro Pro Pro Cys Pro Ala Leu 35 40 45 Leu Tyr Phe Ala Val Glu Thr Gly Phe His His Val Gly Gln Ala Gly 50 55 60 Leu Glu Leu Leu Thr Ser Gly Asn Pro Ala Pro Pro Arg Pro Pro Lys 65 70 75 80 Val Leu 169 103 PRT Homo sapien 169 Met Ala Ile Phe Ser Ala Leu Ser Gln Leu Leu Glu His Gly Leu Asp 1 5 10 15 Leu Glu Thr Ser Asn Lys Asp Phe Thr Ser Ile Pro Ala Ala Cys Trp 20 25 30 Trp Val Ile Ile Ser Met Thr Thr Val Gly Tyr Gly Asp Met Tyr Pro 35 40 45 Ile Thr Val Pro Gly Arg Ile Leu Gly Gly Val Cys Val Val Ser Gly 50 55 60 Ile Val Leu Leu Ala Leu Pro Ile Thr Phe Ile Tyr His Ser Phe Val 65 70 75 80 Gln Cys Tyr His Glu Leu Lys Phe Arg Ser Ala Arg Tyr Ser Arg Ser 85 90 95 Leu Ser Thr Glu Phe Leu Asn 100 170 131 PRT Homo sapien 170 Arg Thr Ala Arg His Asp Tyr Ala Ser Cys Arg His Leu Met Val Phe 1 5 10 15 Ser Thr Arg Leu Thr Leu Lys Arg Cys Tyr Arg Glu Met Val Met Leu 20 25 30 Leu Val Phe Ile Cys Val Ala Met Ala Ile Phe Ser Ala Leu Ser Gln 35 40 45 Leu Leu Glu His Gly Leu Asp Leu Glu Thr Ser Asn Lys Asp Phe Thr 50 55 60 Ser Ile Pro Ala Ala Leu Leu Trp Val Ile Ile Ser Met Thr Thr Val 65 70 75 80 Gly Tyr Gly Asp Met Tyr Pro Ile Thr Val Pro Gly Arg Ile Leu Gly 85 90 95 Gly Val Cys Val Val Ser Gly Ile Val Leu Leu Ala Leu Pro Ile Thr 100 105 110 Phe Ile Tyr His Ser Phe Val Gln Cys Tyr His Glu Leu Lys Phe Arg 115 120 125 Ser Ala Arg 130 171 23 PRT Homo sapien 171 Met Val Ala His Cys Ser Leu Pro Val Pro Val Thr Leu Pro Asn Cys 1 5 10 15 Pro Val Ala Cys Arg Leu Ala 20 172 57 PRT Homo sapien 172 Met Asn Gly Arg Gly Leu Ala Arg Gln Gly Cys Glu Ser Gly Asn Ala 1 5 10 15 Phe Phe Thr Pro Met Asn Phe Cys Leu Ile Leu Thr Thr Glu Gln Glu 20 25 30 Cys Ser Glu Thr Glu Val Gly Val Thr Asn Ile His Phe Pro Phe Ser 35 40 45 Ser Cys Ser Asn Gln Tyr Phe Lys Lys 50 55 173 50 PRT Homo sapien 173 Met Ser Gly Glu Arg Thr Asp Tyr Ala Pro Leu Asn Asn Lys Leu Cys 1 5 10 15 Ser Arg Val Arg Ala Val Ser Ser Glu Ala Leu Leu Thr Glu Thr Ala 20 25 30 Thr Phe Lys Pro Asn Gln Arg Lys Tyr Leu Trp Asn Ser Leu Pro Gln 35 40 45 Phe Gly 50 174 31 PRT Homo sapien 174 Met Val Thr Asn Leu Leu Thr Ala Gln Cys Gly Trp Met Val Ala Ala 1 5 10 15 Arg Cys Phe Cys Cys Leu Asn Leu Leu Asn Cys Leu Ile Phe Ser 20 25 30 175 456 PRT Homo sapien 175 Met Glu Pro Arg Cys Pro Pro Pro Cys Gly Cys Cys Glu Arg Leu Val 1 5 10 15 Leu Asn Val Ala Gly Leu Arg Phe Glu Thr Arg Ala Arg Thr Leu Gly 20 25 30 Arg Phe Pro Asp Thr Leu Leu Gly Asp Pro Ala Arg Arg Gly Arg Phe 35 40 45 Tyr Asp Asp Ala Arg Arg Glu Tyr Phe Phe Asp Arg His Arg Pro Ser 50 55 60 Phe Asp Ala Val Leu Tyr Tyr Tyr Gln Ser Gly Gly Arg Leu Arg Arg 65 70 75 80 Pro Ala His Val Pro Leu Asp Val Phe Leu Glu Glu Val Ala Phe Tyr 85 90 95 Gly Leu Gly Ala Ala Ala Leu Ala Arg Leu Arg Glu Asp Glu Gly Cys 100 105 110 Pro Val Pro Pro Glu Arg Pro Leu Pro Arg Arg Ala Phe Ala Arg Gln 115 120 125 Leu Trp Leu Leu Phe Glu Phe Pro Glu Ser Ser Gln Ala Ala Arg Val 130 135 140 Leu Ala Val Val Ser Val Leu Val Ile Leu Val Ser Ile Val Val Phe 145 150 155 160 Cys Leu Glu Thr Leu Pro Asp Phe Arg Asp Asp Arg Asp Gly Thr Gly 165 170 175 Leu Ala Ala Ala Ala Ala Ala Gly Pro Phe Pro Ala Pro Leu Asn Gly 180 185 190 Ser Ser Gln Met Pro Gly Asn Pro Pro Arg Leu Pro Phe Asn Asp Pro 195 200 205 Phe Phe Val Val Glu Thr Leu Cys Ile Cys Trp Phe Ser Phe Glu Leu 210 215 220 Leu Val Arg Leu Leu Val Cys Pro Ser Lys Ala Ile Phe Phe Lys Asn 225 230 235 240 Val Met Asn Leu Ile Asp Phe Val Ala Ile Leu Pro Tyr Phe Val Ala 245 250 255 Leu Gly Thr Glu Leu Ala Arg Gln Arg Gly Val Gly Gln Gln Ala Met 260 265 270 Ser Leu Ala Ile Leu Arg Val Ile Arg Leu Val Arg Val Phe Arg Ile 275 280 285 Phe Lys Leu Ser Arg His Ser Lys Gly Leu Gln Ile Leu Gly Gln Thr 290 295 300 Leu Arg Ala Ser Met Arg Glu Leu Gly Leu Leu Ile Phe Phe Leu Phe 305 310 315 320 Ile Gly Val Val Leu Phe Ser Ser Ala Val Tyr Phe Ala Glu Val Asp 325 330 335 Arg Val Asp Ser His Phe Thr Ser Ile Pro Glu Ser Phe Trp Trp Ala 340 345 350 Val Val Thr Met Thr Thr Val Gly Tyr Gly Asp Met Ala Pro Val Thr 355 360 365 Val Gly Gly Lys Ile Val Gly Ser Leu Cys Ala Ile Ala Gly Val Leu 370 375 380 Thr Ile Ser Leu Pro Val Pro Val Ile Val Ser Asn Phe Ser Tyr Phe 385 390 395 400 Tyr His Arg Glu Thr Glu Gly Glu Glu Ala Gly Met Phe Ser His Val 405 410 415 Asp Met Gln Pro Cys Gly Pro Leu Glu Gly Lys Ala Asn Gly Gly Leu 420 425 430 Val Asp Gly Glu Val Pro Glu Leu Pro Pro Pro Leu Trp Ala Pro Pro 435 440 445 Gly Lys His Leu Val Thr Glu Val 450 455 176 28 PRT Homo sapien 176 Met Ser Tyr Asn Ser Lys Leu Glu Ser Ile Arg Leu Lys Arg Val Ser 1 5 10 15 Met Lys Thr Ile Pro Lys Ile Pro Phe Thr Gln Asn 20 25 177 91 PRT Homo sapien 177 Met Ala Leu Gly Ser Met Tyr Leu Val Leu Thr Leu Ile Val Ala Glu 1 5 10 15 Val Leu Arg Gly Ala Glu Pro Cys Cys Gly Pro Leu Lys Tyr Arg Val 20 25 30 Leu Arg Pro Cys Pro Leu Pro Val His Cys Ala Pro Pro His His Gln 35 40 45 Pro Ser Arg Gly Asn Pro Val Ala Cys Leu Pro Thr Tyr Lys Val Val 50 55 60 Tyr Gln Ala Ala Val Leu Ala Thr Ala Phe Lys Phe Gln Cys Asp Leu 65 70 75 80 Pro Gly Arg Ser Ile Thr Leu Arg Arg Ser Ala 85 90 178 54 PRT Homo sapien 178 Met Lys Phe Ser Ser Ala Phe Val Gln Ser Lys Pro Leu Ser Ser Cys 1 5 10 15 Arg Ala Glu Thr Leu Tyr Met Lys Thr Val Ser Glu Leu Val Leu Ala 20 25 30 Ser Ile His Glu Asn Cys Leu Ser Cys Met Leu Ala Lys Thr Ser Ser 35 40 45 Glu Thr Lys Lys Leu Lys 50 179 88 PRT Homo sapien 179 Gly Arg Val Arg Phe Val Val Glu Leu Ala Asp Pro Lys Leu Glu Val 1 5 10 15 Lys Trp Tyr Lys Asn Gly Gln Glu Ile Arg Pro Ser Thr Lys Tyr Ile 20 25 30 Phe Glu His Lys Gly Cys Gln Arg Ile Leu Phe Ile Asn Asn Cys Gln 35 40 45 Met Thr Asp Asp Ser Glu Tyr Tyr Val Thr Ala Gly Asp Ala Lys Cys 50 55 60 Ser Thr Glu Leu Phe Val Arg Glu Pro Pro Phe Met Val Pro Ser Ser 65 70 75 80 Trp Ile Glu Thr Pro Ala Asp Cys 85 180 26 PRT Homo sapien 180 Met Val Leu Tyr Ser Glu Gly His Gln His Gly Pro His Leu Leu Asn 1 5 10 15 Met Glu Asn Gln Asn Leu Asn Glu Tyr Asn 20 25 181 57 PRT Homo sapien 181 Met Thr Glu Arg Ala Asp Gly Lys Ser Gln Ser Cys Ile Glu Glu Ile 1 5 10 15 Ser Met Val Ala Leu Lys Leu Leu Lys Pro Asp Val Ser Ser Ala Ser 20 25 30 His Trp Lys Met Asp Arg Trp Ala Asn His His Leu Thr Ser Gln Arg 35 40 45 Glu Gly Gln Cys Ala Lys Val Phe Lys 50 55 182 67 PRT Homo sapien 182 Met Asn Thr Lys Ala Leu Pro Thr Thr Pro Ala Gln Thr Ala Ile Ser 1 5 10 15 Pro Pro Glu Gly Gln Cys Ser Ser Ser Ile Gly Leu Glu Thr Ile Pro 20 25 30 Glu Ser Pro Cys Phe Arg Thr Pro Glu Ser Ser Asn Ser Pro Ser Leu 35 40 45 Arg Arg Asp Leu Leu Ala Ala Lys Arg Val Lys Leu Ile Val Leu Gln 50 55 60 Ser Ser Ala 65 183 91 PRT Homo sapien 183 Asp Val Gly Gly Ala Gln Val Leu Ala Thr Gly Lys Thr Pro Gly Ala 1 5 10 15 Glu Ile Asp Phe Lys Tyr Ala Leu Ile Gly Thr Ala Val Gly Val Ala 20 25 30 Ile Ser Ala Gly Phe Leu Ala Leu Lys Ile Cys Met Ile Arg Arg His 35 40 45 Leu Phe Asp Asp Asp Ser Ser Asp Leu Lys Ser Thr Pro Gly Gly Leu 50 55 60 Ser Asp Thr Ile Pro Leu Lys Lys Arg Ala Pro Arg Arg Asn His Asn 65 70 75 80 Phe Ser Lys Arg Asp Ala Gln Val Ile Glu Leu 85 90 184 101 PRT Homo sapien 184 Met Arg Pro Gly Arg Tyr Gln Ala Pro Arg Pro Phe Leu Tyr His Gly 1 5 10 15 Cys Trp Val Thr Ser Gly Ser His His Leu Phe Pro Ser Leu Phe Pro 20 25 30 Ile Ser Gln Met Trp Gly His Gly Leu Asp Asp Gly Leu His Arg Ser 35 40 45 Phe His Leu Cys Glu Ser Lys Ser Gly Gln Ser Ala Arg Thr His Leu 50 55 60 Cys Pro Gly Ser Ala Pro Gln Asn Gln Pro Pro Ala Ser Leu Lys Gln 65 70 75 80 Lys Pro His Leu Lys Gly Cys Ser Glu Glu Ser Thr Phe Ser Met Ser 85 90 95 Cys Cys Trp Lys Ile 100 185 489 PRT Homo sapien 185 Gly Trp Thr Val Ile Gln Asn Arg Gln Asp Gly Ser Val Asp Phe Gly 1 5 10 15 Arg Lys Trp Asp Pro Tyr Lys Gln Gly Phe Gly Asn Val Ala Thr Asn 20 25 30 Thr Asp Gly Lys Asn Tyr Cys Gly Leu Pro Gly Asn Glu Gln Ala Cys 35 40 45 Lys Ile Lys Ser Phe Tyr Leu Lys Trp Asp Phe Phe Ala Leu Lys Asn 50 55 60 Ile His Cys Trp Lys Pro Val Leu Gly Ser Ala Glu Glu Phe Pro Asp 65 70 75 80 Lys Asn Val Glu Ala Lys Asp Lys Gly Arg Lys Ala Val Phe Ser Phe 85 90 95 Pro Lys Phe Tyr Phe Trp Ala Glu Ile Leu Phe Cys Phe Ser Phe Gly 100 105 110 Glu Tyr Trp Leu Gly Asn Asp Lys Ile Ser Gln Leu Thr Arg Met Gly 115 120 125 Pro Thr Glu Leu Leu Ile Glu Met Glu Asp Trp Lys Gly Asp Lys Val 130 135 140 Lys Ala His Tyr Gly Gly Phe Thr Val Gln Asn Glu Ala Asn Lys Tyr 145 150 155 160 Gln Ile Ser Val Asn Lys Tyr Arg Gly Thr Ala Gly Asn Ala Leu Met 165 170 175 Asp Gly Ala Ser Gln Leu Met Gly Glu Asn Arg Thr Met Thr Ile His 180 185 190 Asn Gly Met Phe Phe Ser Thr Tyr Asp Arg Asp Asn Asp Gly Trp Tyr 195 200 205 Val Trp His Ser Leu Leu Leu Leu Ala Lys Ser His Ala Tyr His Tyr 210 215 220 Ser Glu Ser Leu Thr Ile Phe Leu Ile Ala Thr Thr Ser Trp Ala Leu 225 230 235 240 Thr Val Ser His Cys Pro Lys Leu Phe Met His His Ser Lys Ala Phe 245 250 255 Gln Leu Ala Gly Arg His Ser Tyr Ser His Phe Thr Asp Glu Ile Ala 260 265 270 Arg Asp Tyr Val Ile Cys Pro Met Ser His Asn Tyr Pro Glu Ile Lys 275 280 285 Leu Glu Phe Glu His Ser Tyr Phe Leu Asn Asn Glu His Leu Asp Lys 290 295 300 Tyr Leu Tyr Leu Tyr Ile Leu Lys Cys Val Ala Lys Leu Ser Phe Ser 305 310 315 320 Phe Pro Gly Phe Ser Asp Thr Lys Gly Cys Lys Ser Tyr Tyr Ser Ser 325 330 335 Ile Lys Ala Gln Thr Gln Ser Leu Asp Gly Leu Pro Gln Arg Pro Ser 340 345 350 Tyr Leu Ser Phe Leu Leu Ala Gly Thr Gly Gly Leu Trp Cys Ile Ser 355 360 365 Val Thr Leu Cys Ile Ala Pro Lys Gly Lys Thr Thr Val His Thr Ser 370 375 380 Val Ala Val Phe Tyr Gly Ala Ser Ala Lys Arg Asn Leu Thr Thr Val 385 390 395 400 Val Leu Phe Leu Ile Thr Pro Asn Thr Phe Ser Phe Arg Leu Thr Ser 405 410 415 Asp Pro Arg Lys Gln Cys Ser Lys Glu Asp Gly Gly Gly Trp Trp Tyr 420 425 430 Asn Arg Cys His Ala Ala Asn Pro Asn Gly Arg Tyr Tyr Trp Gly Gly 435 440 445 Gln Tyr Thr Trp Asp Met Ala Lys His Gly Thr Asp Asp Gly Val Val 450 455 460 Trp Met Asn Trp Lys Gly Ser Trp Tyr Ser Met Arg Lys Met Ser Met 465 470 475 480 Lys Ile Arg Pro Phe Phe Pro Gln Gln 485 186 33 PRT Homo sapien 186 Met Val Thr Glu Ser Leu Ser Ser Pro His Ser Glu Ser Ile Pro Leu 1 5 10 15 Gly Arg Val Asn Pro Gly Ser Gly Leu Pro Pro His Ser Thr Arg Pro 20 25 30 Phe 187 149 PRT Homo sapien 187 Pro Gly Asn Leu Asp Thr Ser Ser Arg Gly Ser Ser Gly Ser Pro Ala 1 5 10 15 His Ala Glu Ser Tyr Ser Ser Gly Gly Gly Gly Gln Gln Lys Phe Arg 20 25 30 Val Asp Met Pro Gly Ser Gly Ser Ala Phe Ile Pro Thr Ile Asn Ala 35 40 45 Ile Thr Thr Ser Gln Asp Leu Gln Trp Met Val Gln Pro Thr Val Ile 50 55 60 Thr Ser Met Ser Asn Pro Tyr Pro Arg Ser His Pro Tyr Ser Pro Leu 65 70 75 80 Pro Gly Leu Ala Ser Val Ala Gly His Met Ala Leu Pro Arg Pro Gly 85 90 95 Val Ile Lys Thr Ile Gly Thr Thr Val Gly Arg Arg Arg Arg Asp Glu 100 105 110 Gln Leu Ser Pro Glu Glu Glu Glu Lys Arg Arg Ile Arg Arg Glu Arg 115 120 125 Asn Lys Leu Ala Ala Ala Lys Cys Arg Asn Arg Arg Arg Glu Leu Thr 130 135 140 Glu Lys Leu Gln Ala 145 188 41 PRT Homo sapien 188 Met Thr Val Pro Leu His Thr Ser Leu Ser Tyr Arg Gly Arg Ser Gln 1 5 10 15 Leu Leu Lys Thr Lys Thr Thr Ile Asn Ile Tyr Lys Asn His Asn Ile 20 25 30 Lys Gly Phe Met Leu Arg Lys Asn Pro 35 40 189 45 PRT Homo sapien 189 Met Tyr Thr Asn Lys Tyr Ala Gln Asp Leu Glu Ser Tyr Ile Lys Met 1 5 10 15 Tyr Leu Thr Trp Leu Glu Cys Val Cys Val Phe Pro Arg Leu Ser Lys 20 25 30 Ile Arg Lys Pro Glu Ser Gln Ala Thr Lys Lys Lys Asn 35 40 45 190 91 PRT Homo sapien 190 Met Phe Leu Cys Asn Val Leu Arg Val Thr Trp Ala Ser Pro Thr Tyr 1 5 10 15 Ala Ser Thr Val Cys Cys Val Thr Phe Arg Gln Leu His Thr Pro Pro 20 25 30 Ala Pro Leu Pro Ser Pro Pro Ser Ser His Thr Val Ser Ala Gly Cys 35 40 45 Gly Ser Pro Thr Ser Val Met Ser Gly Ile Met Leu Leu Leu Ser Leu 50 55 60 Leu Phe Ser Leu Phe Phe Phe Phe Val Ile Gln Val Leu Leu Thr Ser 65 70 75 80 Ser Leu Ile His Gln Asn Ala Arg Ser Ser Tyr 85 90 191 100 PRT Homo sapien 191 Ala Asp Asn Asp Ile Gly Ala Val Ser Thr Thr Gly His Gly Glu Ser 1 5 10 15 Ile Leu Lys Val Asn Leu Ala Arg Leu Thr Leu Phe His Ile Glu Gln 20 25 30 Gly Lys Thr Val Glu Glu Ala Ala Asp Leu Ser Leu Gly Tyr Met Lys 35 40 45 Ser Arg Val Lys Gly Leu Gly Gly Leu Ile Val Val Ser Lys Thr Gly 50 55 60 Asp Trp Val Ala Lys Trp Thr Ser Thr Ser Met Pro Trp Ala Ala Ala 65 70 75 80 Lys Asp Gly Lys Leu His Phe Gly Ile Asp Pro Asp Asp Thr Thr Ile 85 90 95 Thr Asp Leu Pro 100 192 54 PRT Homo sapien 192 Met Glu Glu Gln Glu Glu Ala Leu Cys Ser His His Ile Pro Val Ala 1 5 10 15 Arg Ser Trp Leu Gln Gly Ser Ser Gly Asn Arg Ile Pro Arg Ser His 20 25 30 Glu Thr Ser Pro Asn Ser Ala Val Thr Glu Ser Thr Arg Gln Trp Leu 35 40 45 Lys Asp Gly Glu Thr Ser 50 193 63 PRT Homo sapien 193 Met Ile Ile Leu Lys Tyr Arg Trp Lys Asp Thr Asn Ala Arg Lys Arg 1 5 10 15 Glu Ser Asn Gln Pro Arg Phe Gly Gly Trp Gly Thr Glu Asp Gly Ala 20 25 30 Thr Phe Pro Pro Tyr Leu Leu Phe Phe Tyr Ile Pro Ile Cys Thr Leu 35 40 45 Arg Ile His Leu Arg Ser Ser Phe Lys Arg Glu Lys Leu Asp Thr 50 55 60 194 211 PRT Homo sapien 194 Met Val Phe Leu Lys Phe Phe Cys Met Ser Phe Phe Cys His Leu Cys 1 5 10 15 Gln Gly Tyr Phe Asp Gly Pro Leu Tyr Pro Glu Met Ser Asn Gly Thr 20 25 30 Leu His His Tyr Phe Val Pro Asp Gly Asp Tyr Glu Glu Asn Asp Asp 35 40 45 Pro Glu Lys Cys Gln Leu Leu Phe Arg Val Ser Asp His Arg Arg Cys 50 55 60 Ser Gln Gly Glu Gly Ser Gln Val Gly Ser Leu Leu Ser Leu Thr Leu 65 70 75 80 Arg Glu Glu Phe Thr Val Leu Gly Arg Gln Val Glu Asp Ala Gly Arg 85 90 95 Val Leu Glu Gly Ile Ser Lys Ser Ile Ser Tyr Asp Leu Asp Gly Glu 100 105 110 Glu Ser Tyr Gly Lys Tyr Leu Arg Arg Glu Ser His Gln Ile Gly Asp 115 120 125 Ala Tyr Ser Asn Ser Asp Lys Ser Leu Thr Glu Leu Glu Ser Lys Phe 130 135 140 Lys Gln Gly Gln Glu Gln Asp Ser Arg Gln Glu Ser Arg Leu Asn Glu 145 150 155 160 Asp Phe Leu Gly Met Leu Val His Thr Arg Ser Leu Leu Lys Glu Thr 165 170 175 Leu Asp Ile Ser Val Gly Leu Arg Asp Lys Tyr Glu Leu Leu Ala Leu 180 185 190 Thr Ile Arg Ser His Gly Thr Arg Leu Gly Arg Leu Lys Asn Asp Tyr 195 200 205 Leu Lys Val 210 195 54 PRT Homo sapien 195 Met Asp Asp Ser Lys Leu Gln Lys Lys Lys Asp Val Asp Lys His Cys 1 5 10 15 Leu Thr Glu His Phe Ile Phe Ser Gln Leu Phe Trp Phe Leu Leu Ile 20 25 30 Thr Met Thr Lys Met Leu Asp Ser Glu Leu Cys Arg Tyr Phe Ser Lys 35 40 45 Phe Tyr Asp Phe Lys Ser 50 196 88 PRT Homo sapien 196 Met Leu Gly Leu Gln Thr Leu Ser Arg Phe Leu Ser Gly His Pro Gly 1 5 10 15 Phe Leu Thr His Cys Leu Lys Ser Arg Trp Gln Val Pro Ser Leu Asn 20 25 30 His Ser Cys Ala Pro Glu Asp Ser Gly Pro Lys Leu Pro Ser Ser Ala 35 40 45 Cys His Ser Leu Leu Ile Ile Ser Ser Ser Asp Gln Val Cys Val Met 50 55 60 His Leu Ala Gln Ala Gln Gly Val Pro Arg Arg Asp His Asp Pro Ser 65 70 75 80 His Cys Ala Arg Ser Ser Ser Ile 85 197 48 PRT Homo sapien 197 Met Thr Glu Met Thr Gln Ser Lys Gly Arg Ile Gly Thr Glu Asp Ala 1 5 10 15 Asn Thr Gly Ser Tyr Lys Ile Gln Arg Glu Leu Ser Gly Gly Lys Thr 20 25 30 Gln Glu Pro Asn Ser Thr His Leu Ile Pro Leu Val Asp Gln Leu Asn 35 40 45 198 121 PRT Homo sapien 198 Phe Phe Ala Asp Glu Val Ser Arg Leu Ser Pro Gly Leu Glu Cys Ser 1 5 10 15 Gly Val Ile Ser Ala His Cys Asn Phe His Leu Leu Gly Ser Ser Ser 20 25 30 Ser Pro Ala Ser Ala Ser Gln Val Ala Glu Ile Thr Gly Ala Cys His 35 40 45 Pro Thr Trp Leu Ile Phe Val Ile Leu Val Glu Thr Gly Phe His His 50 55 60 Val Gly Gln Ala Asp Ala Leu Leu Thr Ser Gly Asp Pro Pro Phe Ser 65 70 75 80 Ala Ser Gln Ser Ala Gly Ile Thr Gly Val Ser His Arg Ala Arg Pro 85 90 95 Ala Asn Thr Phe Ala Leu Thr Thr Leu Gly Leu Leu Tyr Lys Ile Val 100 105 110 Met Ile Ala Met Glu Val Leu Pro Pro 115 120 199 162 PRT Homo sapien 199 Met Asp Ala Ala Gly Gln Val Leu Gly Pro Glu Arg Gly Gly Tyr Leu 1 5 10 15 Pro His Trp Val Ala Ser Ser Ala Ala Pro His Leu Ser Leu Phe Ser 20 25 30 Pro Lys Leu Val Phe Leu Thr Ile Ile Val Val Gly Gly Gly Gln Met 35 40 45 Leu Lys Val Glu Ala Asp Leu Glu Lys Glu Thr His Gly Val Thr Val 50 55 60 Ala Lys Asp Ser Trp Lys Arg Asn Ser Ile Thr Ser Ser Leu Ala Thr 65 70 75 80 Thr Arg His Pro Arg Pro Trp His Ser Gln Arg Leu Cys Ala Val Ala 85 90 95 Lys Pro Leu Asn Leu Phe Trp Pro Cys Val Leu Gln Arg Ser Leu Cys 100 105 110 Cys Lys Thr Val Asp Ser Phe Asp Glu Val Leu Lys Asn Ala Thr Arg 115 120 125 Gly Gly Gly Val Trp Leu Ala Val Trp Pro Ser Ser Glu Lys Val Ala 130 135 140 Glu Ile Arg Gly Gln Gly Cys His Ser Pro Arg Leu Ser Ser Gly Ser 145 150 155 160 Gln Ser 200 594 PRT Homo sapien 200 Val Pro Gly Arg Lys Leu His Arg Ser Arg Leu Gln Ala Ala Ala Pro 1 5 10 15 Arg Pro Ser Thr Cys Ala Gln Ser Leu Cys Trp Ser Arg Pro Pro Ala 20 25 30 Ala Gly Thr Gly Thr Gly Asp Pro Ser Gln Ser Lys Ala Pro Thr Met 35 40 45 Ala Met Gly Leu Phe Arg Val Cys Leu Val Val Val Thr Ala Ile Ile 50 55 60 Asn His Pro Leu Leu Phe Pro Arg Glu Asn Ala Thr Val Pro Glu Asn 65 70 75 80 Glu Glu Glu Ile Ile Arg Lys Met Gln Ala His Gln Glu Lys Leu Gln 85 90 95 Leu Glu Gln Leu Arg Leu Glu Glu Glu Val Ala Arg Leu Ala Ala Glu 100 105 110 Lys Glu Ala Leu Glu Gln Val Ala Glu Glu Gly Arg Gln Gln Asn Glu 115 120 125 Thr Arg Val Ala Trp Asp Leu Trp Ser Thr Leu Cys Met Ile Leu Phe 130 135 140 Leu Met Ile Glu Val Trp Arg Gln Asp His Gln Glu Gly Pro Ser Pro 145 150 155 160 Glu Cys Leu Gly Gly Glu Glu Asp Glu Leu Pro Gly Leu Gly Gly Ala 165 170 175 Pro Leu Gln Gly Leu Thr Leu Pro Asn Lys Ala Thr Leu Gly His Phe 180 185 190 Tyr Glu Arg Cys Ile Arg Gly Ala Thr Ala Asp Ala Ala Arg Thr Arg 195 200 205 Glu Phe Leu Glu Gly Phe Val Asp Asp Leu Leu Glu Ala Leu Arg Ser 210 215 220 Leu Cys Asn Arg Asp Thr Asp Met Glu Val Glu Asp Phe Ile Gly Val 225 230 235 240 Asp Ser Met Tyr Glu Asn Trp Gln Val Asp Arg Pro Leu Leu Cys His 245 250 255 Leu Phe Val Pro Phe Thr Pro Pro Glu Pro Tyr Arg Phe His Pro Glu 260 265 270 Leu Trp Cys Ser Gly Arg Ser Val Pro Leu Asp Arg Gln Gly Tyr Gly 275 280 285 Gln Ile Lys Val Val Arg Ala Asp Gly Asp Thr Leu Ser Cys Ile Cys 290 295 300 Gly Lys Thr Lys Leu Gly Glu Asp Met Leu Cys Leu Leu His Gly Arg 305 310 315 320 Asn Ser Met Ala Pro Pro Cys Gly Asp Met Glu Asn Leu Leu Cys Ala 325 330 335 Thr Asp Ser Leu Tyr Leu Asp Thr Met Gln Val Met Lys Trp Phe Gln 340 345 350 Thr Ala Leu Thr Arg Ala Trp Lys Gly Ile Ala His Lys Tyr Glu Phe 355 360 365 Asp Leu Ala Phe Gly Gln Leu Asp Ser Pro Gly Ser Leu Lys Ile Lys 370 375 380 Phe Arg Ser Gly Lys Phe Met Pro Phe Asn Leu Ile Pro Val Ile Gln 385 390 395 400 Cys Asp Asp Ser Asp Leu Tyr Phe Val Ser His Leu Pro Arg Glu Pro 405 410 415 Ser Glu Gly Thr Pro Ala Ser Ser Thr Asp Trp Leu Leu Ser Phe Ala 420 425 430 Val Tyr Glu Arg His Phe Leu Arg Thr Thr Leu Lys Ala Leu Pro Glu 435 440 445 Gly Ala Cys His Leu Ser Cys Leu Gln Ile Ala Ser Phe Leu Leu Ser 450 455 460 Lys Gln Ser Arg Leu Thr Gly Pro Ser Gly Leu Ser Ser Tyr His Leu 465 470 475 480 Lys Thr Ala Leu Leu His Leu Leu Leu Leu Arg Gln Ala Ala Asp Trp 485 490 495 Lys Ala Gly Gln Leu Asp Ala Arg Leu His Glu Leu Leu Cys Phe Leu 500 505 510 Glu Lys Ser Leu Leu Gln Lys Lys Leu His His Phe Phe Ile Gly Asn 515 520 525 Arg Lys Val Pro Glu Ala Met Gly Leu Pro Glu Ala Val Leu Arg Ala 530 535 540 Glu Pro Leu Asn Leu Phe Arg Pro Phe Val Leu Gln Arg Ser Leu Tyr 545 550 555 560 Arg Lys Thr Leu Asp Ser Phe Tyr Glu Met Leu Lys Asn Ala Pro Ala 565 570 575 Leu Ile Ser Glu Tyr Ser Leu His Val Pro Ser Asp Gln Pro Thr Pro 580 585 590 Lys Ser 201 38 PRT Homo sapien 201 Met Ser Leu His Ala Glu Val Gly Gly Ala Leu Lys Pro Val Ile Tyr 1 5 10 15 Ala Val Lys Thr Lys Trp Val Cys Tyr Leu Ile Ser Trp Gly Ile His 20 25 30 Gly Leu Ala Val Pro Gly 35 202 16 PRT Homo sapien 202 Met Glu Arg Ile Gly Thr Phe Tyr Ser Gly Asn Thr Gln Pro Ala Thr 1 5 10 15 203 87 PRT Homo sapien 203 Met Ala Glu Gly Val Gly Ala Gly Thr Leu Glu Ala Pro Pro Leu Leu 1 5 10 15 Ser Leu Pro Ser Ala Ser Pro Val Pro Pro Ala Ala Leu Val Thr Val 20 25 30 Ser Asp Gly Tyr Leu Pro Gly Phe Val Ala Ser Leu Ser Val Phe Ser 35 40 45 Cys Ser Asp Pro Leu Ala Gly Trp Leu Arg Lys Lys Lys Met Cys Phe 50 55 60 Arg Cys His Cys Asn Pro Gly His Gln Gly Asn Pro Ser Phe Pro Phe 65 70 75 80 Leu Ile Cys Ser Pro Arg Thr 85 204 252 PRT Homo sapien 204 Met Ser Ile Tyr Lys Glu Pro Pro Pro Gly Met Phe Val Val Pro Asp 1 5 10 15 Thr Val Asp Met Thr Lys Ile His Ala Leu Ile Thr Gly Pro Phe Asp 20 25 30 Thr Pro Tyr Glu Gly Gly Phe Phe Leu Phe Val Phe Arg Cys Pro Pro 35 40 45 Asp Tyr Pro Ile His Pro Pro Arg Val Lys Leu Met Thr Thr Gly Asn 50 55 60 Asn Thr Val Arg Phe Asn Pro Asn Phe Tyr Arg Asn Gly Lys Val Cys 65 70 75 80 Leu Ser Ile Leu Gly Thr Trp Thr Gly Pro Ala Trp Ser Pro Ala Gln 85 90 95 Ser Ile Ser Ser Val Leu Ile Ser Ile Gln Ser Leu Met Thr Glu Asn 100 105 110 Pro Tyr His Asn Glu Pro Gly Phe Glu Gln Glu Arg His Pro Gly Asp 115 120 125 Ser Lys Asn Tyr Asn Glu Cys Ile Arg His Glu Thr Ile Arg Val Ala 130 135 140 Val Cys Asp Met Met Glu Gly Lys Cys Pro Cys Pro Glu Pro Leu Arg 145 150 155 160 Gly Val Met Glu Lys Ser Phe Leu Glu Tyr Tyr Asp Phe Tyr Glu Val 165 170 175 Ala Cys Lys Asp Arg Leu His Leu Gln Gly Gln Thr Met Gln Asp Pro 180 185 190 Phe Gly Glu Lys Arg Gly His Phe Asp Tyr Gln Ser Leu Leu Met Arg 195 200 205 Leu Gly Leu Ile Arg Gln Lys Val Leu Glu Arg Leu His Asn Glu Asn 210 215 220 Ala Glu Met Asp Ser Asp Ser Ser Ser Ser Gly Thr Glu Thr Asp Leu 225 230 235 240 His Gly Ser Leu Arg Val His Gly Ser Leu Arg Val 245 250 205 91 PRT Homo sapien 205 Met Leu Thr Pro Ala Arg Pro Ser Cys His Thr Leu Ser Gly Arg Ser 1 5 10 15 Met Ala Tyr Arg Met Lys Arg Gly Thr Arg Asn Pro Cys Gly Arg Gly 20 25 30 Leu Asp Leu Lys Gln Cys Pro Leu Trp Leu Leu Leu Pro Trp Leu Thr 35 40 45 Gly Phe Leu Asp His Val His Phe Thr Gly Pro Trp Asp Leu His Leu 50 55 60 Leu Ala Ser Pro Ala Gly Leu Ile Pro Ala Arg Ala Pro Ser Phe Leu 65 70 75 80 Leu Met Val Phe Arg Trp Pro Asp His Gly Lys 85 90 206 213 PRT Homo sapien 206 Ser Pro His Gln Ala Ala Ala Pro Val Asp Gln Thr Pro Arg Thr Leu 1 5 10 15 Ala Thr Met Gly Gln Arg Ala Leu Pro Ser Ser Leu Ala Leu Leu Ser 20 25 30 Arg Pro Leu Ser Pro Pro Pro Ala Ala Cys Ser Gly Asp Pro Gly Cys 35 40 45 Gly Ser Gly Ala Gly Leu Pro Ser Ala Ser Ala Ala Ala Gly Ile Ala 50 55 60 Ser Ser Ala Val Glu Ala Val Cys Gly Asp Ala Ala Pro Ala Cys Leu 65 70 75 80 Leu Arg Thr Pro Leu Arg Gly Leu Leu Lys Pro Thr Gly Pro Arg Ser 85 90 95 Thr Met Glu Cys Pro Pro Ala Leu Ile Val His Pro Pro Thr Gly Gly 100 105 110 Met Ala Arg Arg Ala Ala Ser Gln Pro Trp Ala Ala Ala Ser Ala Thr 115 120 125 Pro Met Leu Ser Ser Lys Ala Ser Leu Cys Ile Pro Thr Glu Arg Pro 130 135 140 Pro Pro Gln Pro Leu Met Arg Thr Pro Ala Ala Arg Ser His Trp Pro 145 150 155 160 Ile Pro His Pro Ala Ser Thr Ala Cys Pro Ala Pro Leu Pro Val Val 165 170 175 Leu Val Ala Pro Arg Ser Thr Ile Leu Ser Met Ser Arg Thr Trp Thr 180 185 190 Cys Arg Arg Trp Ala Val Ala Pro Cys Arg Ala Glu Lys Leu Met Cys 195 200 205 Ser Ser Ser Arg Ser 210 207 92 PRT Homo sapien 207 Met Tyr Lys Gly Ala Ala Trp Arg Gly Lys Glu His Asn Lys Thr Pro 1 5 10 15 Leu Glu Val Phe Gln Arg Val Val Ser Gln Ile Ser Leu Ile Gln Glu 20 25 30 Glu Asp Asp Glu Arg Glu Arg Thr Trp Asn Tyr Leu Lys Ser Ser Asn 35 40 45 Ser Leu Val Leu Phe Asn Lys Lys Glu Phe Trp Phe Val Ala Glu Ser 50 55 60 Asp Leu Thr Ala Ala Asn Ser Ser Leu Leu Leu Arg Cys Ile Ser Asn 65 70 75 80 Ser Lys Leu Asp Ala Pro Pro Ser Leu Phe Phe Pro 85 90 208 130 PRT Homo sapien 208 Met Val Cys Glu Asp Ala Pro Ser Phe Gln Met Ala Trp Glu Ser Gln 1 5 10 15 Met Ala Trp Glu Arg Gly Pro Ala Leu Leu Cys Cys Val Leu Ser Ala 20 25 30 Ser Gln Leu Ser Ser Gln Asp Gln Asp Pro Leu Gly His Ile Lys Ser 35 40 45 Leu Leu Tyr Pro Phe Gly Phe Pro Val Glu Leu Pro Arg Pro Gly Pro 50 55 60 Thr Gly Ala Tyr Lys Lys Val Lys Asn Gln Asn Gln Thr Thr Ser Ser 65 70 75 80 Glu Leu Leu Arg Lys Gln Thr Ser His Phe Asn Gln Arg Gly His Arg 85 90 95 Ala Arg Ser Lys Leu Leu Ala Ser Arg Gln Ile Pro Asp Arg Thr Phe 100 105 110 Lys Cys Gly Lys Trp Leu Pro Gln Val Pro Ser Pro Val Val Pro Ser 115 120 125 Pro Val 130 209 63 PRT Homo sapien 209 Met Asn Asp Tyr Gly Leu Gly Leu Gly Phe Ile Thr Asn Pro Ile Ile 1 5 10 15 Asp His Leu Phe Pro Ala Leu Gly Ile Thr Ala Lys Pro Asn Gly Ser 20 25 30 Phe Ser Ile Thr Ala Ser Tyr Asn Phe His Ile Phe Leu Leu Phe Leu 35 40 45 Thr Gly Leu Gln Val Leu Ser Asn Val Leu Lys Leu Phe Asn Val 50 55 60 210 451 PRT Homo sapien 210 Ala Thr Lys Thr Lys Ala Pro Asp Asp Leu Val Ala Pro Val Val Lys 1 5 10 15 Lys Pro His Ile Tyr Tyr Gly Ser Leu Glu Glu Lys Glu Arg Glu Arg 20 25 30 Leu Ala Lys Gly Glu Ser Gly Ile Leu Gly Lys Asp Gly Leu Lys Ala 35 40 45 Gly Ile Glu Ala Gly Asn Ile Asn Ile Thr Ser Gly Glu Val Phe Glu 50 55 60 Ile Glu Glu His Ile Ser Glu Arg Gln Ala Glu Val Leu Ala Glu Phe 65 70 75 80 Glu Arg Arg Lys Arg Ala Arg Gln Ile Asn Val Ser Thr Asp Asp Ser 85 90 95 Glu Val Lys Ala Cys Leu Arg Ala Leu Gly Glu Pro Ile Thr Leu Phe 100 105 110 Gly Glu Gly Pro Ala Glu Arg Arg Glu Arg Leu Arg Asn Ile Leu Ser 115 120 125 Val Val Gly Thr Asp Ala Leu Lys Lys Thr Lys Lys Asp Asp Glu Lys 130 135 140 Ser Lys Lys Ser Lys Glu Glu Tyr Gln Gln Thr Trp Tyr His Glu Gly 145 150 155 160 Pro Asn Ser Leu Lys Val Ala Arg Leu Trp Ile Ala Asn Tyr Ser Leu 165 170 175 Pro Arg Ala Met Lys Arg Leu Glu Glu Ala Arg Leu His Lys Glu Ile 180 185 190 Pro Glu Thr Thr Arg Thr Ser Gln Met Gln Glu Leu His Lys Ser Leu 195 200 205 Arg Ser Leu Asn Asn Phe Cys Ser Gln Ile Gly Asp Asp Arg Pro Ile 210 215 220 Ser Tyr Cys His Phe Ser Pro Asn Ser Lys Met Leu Ala Thr Ala Cys 225 230 235 240 Cys Asp Glu Pro Val Ala Asp Ile Glu Gly His Thr Val Arg Val Ala 245 250 255 Arg Val Met Trp His Pro Ser Gly Arg Phe Leu Gly Thr Thr Cys Tyr 260 265 270 Asp Arg Ser Trp Arg Leu Trp Asp Leu Glu Ala Gln Glu Glu Ile Leu 275 280 285 His Gln Glu Gly His Ser Met Gly Val Tyr Asp Ile Ala Phe His Gln 290 295 300 Asp Gly Ser Leu Ala Gly Thr Gly Gly Leu Asp Ala Phe Gly Arg Val 305 310 315 320 Trp Asp Leu Arg Thr Gly Arg Cys Ile Met Phe Leu Glu Gly His Leu 325 330 335 Lys Glu Ile Tyr Gly Ile Asn Phe Ser Pro Asn Gly Tyr His Ile Ala 340 345 350 Thr Gly Ser Gly Asp Asn Thr Cys Lys Val Trp Asp Leu Arg Gln Arg 355 360 365 Arg Cys Val Tyr Thr Ile Pro Ala His Gln Asn Leu Val Thr Gly Val 370 375 380 Lys Phe Glu Pro Ile His Gly Asn Phe Leu Leu Thr Gly Ala Tyr Asp 385 390 395 400 Asn Thr Ala Lys Ile Trp Thr His Pro Gly Trp Ser Pro Leu Lys Thr 405 410 415 Leu Ala Gly His Glu Gly Lys Val Met Gly Leu Asp Ile Ser Ser Asp 420 425 430 Gly Gln Leu Ile Ala Thr Cys Ser Tyr Asp Arg Thr Phe Lys Leu Trp 435 440 445 Met Ala Glu 450 211 34 PRT Homo sapien 211 Met Glu Ala Gln Gly Cys His Asp Gly Ser Val Val Ile Arg Glu Gly 1 5 10 15 Ala Pro Phe Ile Leu Leu Pro Thr Pro Leu Leu Cys Pro Phe Leu Pro 20 25 30 Leu Ile 212 610 PRT Homo sapien 212 Gly Lys Ala Phe Ile Thr Cys Arg Thr Leu Leu Asn His Lys Ser Ile 1 5 10 15 His Phe Gly Asp Lys Pro Tyr Lys Cys Asp Glu Cys Glu Lys Ser Phe 20 25 30 Asn Tyr Ser Ser Leu Leu Ile Gln His Lys Val Ile His Thr Gly Glu 35 40 45 Lys Pro Tyr Glu Cys Asp Glu Cys Gly Lys Ala Phe Arg Asn Ser Ser 50 55 60 Gly Leu Ile Val His Lys Arg Ile His Thr Gly Glu Lys Pro Tyr Lys 65 70 75 80 Cys Asp Val Cys Gly Lys Ala Phe Ser Tyr Ser Ser Gly Leu Ala Val 85 90 95 His Lys Ser Ile His Pro Gly Lys Lys Ala His Glu Cys Lys Glu Cys 100 105 110 Gly Lys Ser Phe Ser Tyr Asn Ser Leu Leu Leu Gln His Arg Thr Ile 115 120 125 His Thr Gly Glu Arg Pro Tyr Val Cys Asp Val Cys Gly Lys Thr Phe 130 135 140 Arg Asn Asn Ala Gly Leu Lys Val His Arg Arg Leu His Thr Gly Glu 145 150 155 160 Lys Pro Tyr Lys Cys Asp Val Cys Gly Lys Ala Tyr Ile Ser Arg Ser 165 170 175 Ser Leu Lys Asn His Lys Gly Ile His Leu Gly Glu Lys Pro Tyr Lys 180 185 190 Cys Ser Tyr Cys Glu Lys Ser Phe Asn Tyr Ser Ser Ala Leu Glu Gln 195 200 205 His Lys Arg Ile His Thr Arg Glu Lys Pro Phe Gly Cys Asp Glu Cys 210 215 220 Gly Lys Ala Phe Arg Asn Asn Ser Gly Leu Lys Val His Lys Arg Ile 225 230 235 240 His Thr Gly Glu Arg Pro Tyr Lys Cys Glu Glu Cys Gly Lys Ala Tyr 245 250 255 Ile Ser Leu Ser Ser Leu Ile Asn His Lys Ser Val His Pro Gly Glu 260 265 270 Lys Pro Phe Lys Cys Asp Glu Cys Glu Lys Ala Phe Ile Thr Tyr Arg 275 280 285 Thr Leu Thr Asn His Lys Lys Val His Leu Gly Glu Lys Pro Tyr Lys 290 295 300 Cys Asp Val Cys Glu Lys Ser Phe Asn Tyr Thr Ser Leu Leu Ser Gln 305 310 315 320 His Arg Arg Val His Thr Arg Glu Lys Pro Tyr Glu Cys Asp Arg Cys 325 330 335 Glu Lys Val Phe Arg Asn Asn Ser Ser Leu Lys Val His Lys Arg Ile 340 345 350 His Thr Gly Glu Arg Pro Tyr Glu Cys Asp Val Cys Gly Lys Ala Tyr 355 360 365 Ile Ser His Ser Ser Leu Ile Asn His Lys Ser Thr His Pro Gly Lys 370 375 380 Thr Pro His Thr Cys Asp Glu Cys Gly Lys Ala Phe Phe Ser Ser Arg 385 390 395 400 Thr Leu Ile Ser His Lys Arg Val His Leu Gly Glu Lys Pro Phe Lys 405 410 415 Cys Val Glu Cys Gly Lys Ser Phe Ser Tyr Ser Ser Leu Leu Ser Gln 420 425 430 His Lys Arg Ile His Thr Gly Glu Lys Pro Tyr Val Cys Asp Arg Cys 435 440 445 Gly Lys Ala Phe Arg Asn Ser Ser Gly Leu Thr Val His Lys Arg Ile 450 455 460 His Thr Gly Glu Lys Pro Tyr Glu Cys Asp Glu Cys Gly Lys Ala Tyr 465 470 475 480 Ile Ser His Ser Ser Leu Ile Asn His Lys Ser Val His Gln Gly Lys 485 490 495 Gln Pro Tyr Asn Cys Glu Cys Gly Lys Ser Phe Asn Tyr Arg Ser Val 500 505 510 Leu Asp Gln His Lys Arg Ile His Thr Gly Lys Lys Pro Tyr Arg Cys 515 520 525 Asn Glu Cys Ala His Ile Pro Asn Ala Thr Ala Asp Leu Met Lys Val 530 535 540 Asp His Glu Glu Glu Pro Gln Leu Ser Glu Pro Tyr Leu Ser Lys Gln 545 550 555 560 Lys Lys Leu Met Ala Lys Ile Leu Glu His Asp Asp Val Ser Tyr Leu 565 570 575 Lys Lys Ile Leu Gly Glu Leu Ala Met Val Leu Asp Gln Ile Glu Ala 580 585 590 Glu Leu Glu Lys Arg Lys Leu Glu Asn Glu Ala Leu Ser Gln Trp Lys 595 600 605 Glu Phe 610 213 47 PRT Homo sapien 213 Met Cys Ala Lys Trp Gly Glu Ile Gly Ala Gly Lys Pro Ile Pro His 1 5 10 15 Arg Gly Pro Ala Leu Ala Pro Gly Ser Pro His Ala Phe Phe Val Phe 20 25 30 Phe Phe Phe Phe Ala Ser Asp Gln Phe Thr Thr Val Ser Trp Thr 35 40 45 214 25 PRT Homo sapien 214 Met Glu Thr Pro Ser Leu Glu Gly Thr Pro Arg Lys Pro Cys His Gly 1 5 10 15 Leu Leu Ser Leu Ser Ser Leu Leu Leu 20 25 215 29 PRT Homo sapien 215 Met Ser Ser Tyr Gly Met Gln Gly Thr Val Gly Ser Arg Val Ser Ile 1 5 10 15 Leu Pro Thr Arg Ala Gln Gly Gln Ala Gly Glu Val Arg 20 25 216 64 PRT Homo sapien 216 Met Val Thr Leu Asp Leu Leu Glu Arg Ala Gln Cys Asp Gly Ser Trp 1 5 10 15 Ser Arg Arg Gly Thr Pro Leu Leu Phe Tyr Phe Phe Cys Lys Val Leu 20 25 30 Thr Leu Glu Gly Tyr Ser Ile Gln Ser Leu Asn Met Phe Phe Lys Arg 35 40 45 Asn Lys Glu Gln Ala Thr Ala Leu Leu Glu Ile Thr Asn Arg Phe Leu 50 55 60 217 50 PRT Homo sapien 217 Met Glu Pro His Ile Met Lys Phe Asn Ser His Val Lys Thr Phe Cys 1 5 10 15 Ile Val Gly Cys Gln Lys Tyr Phe Pro Asn Phe Arg Leu Thr Cys Arg 20 25 30 Val Gly Asp Gly Leu Pro Pro Tyr Asn Phe Lys Phe Val Ser Gln Ser 35 40 45 Leu Ala 50 218 785 PRT Homo sapien 218 Lys Ala Lys Ile Ser Trp Glu Ala Pro Val Glu Lys Lys Thr Glu Cys 1 5 10 15 Ile Gln Lys Gly Lys Asn Asn Gln Val Gly Ala Trp Thr Leu Leu Leu 20 25 30 Val Leu Pro Ser Pro Gln Asp Val Ser Ser His Ser Gly Pro Arg Ala 35 40 45 Leu Thr Asn Arg Thr Pro Phe Cys Pro Gln Thr Glu Cys Phe Asn Phe 50 55 60 Ile Arg Phe Leu Gln Pro Tyr Asn Ala Ser His Leu Tyr Val Cys Gly 65 70 75 80 Thr Tyr Ala Phe Gln Pro Lys Cys Thr Tyr Val Asn Met Leu Thr Phe 85 90 95 Thr Leu Glu His Gly Glu Phe Glu Asp Gly Lys Gly Lys Cys Pro Tyr 100 105 110 Asp Pro Ala Lys Gly His Ala Gly Leu Leu Val Asp Gly Glu Leu Tyr 115 120 125 Ser Ala Thr Leu Asn Asn Phe Leu Gly Thr Glu Pro Ile Ile Leu Arg 130 135 140 Asn Met Gly Pro His His Ser Met Lys Thr Glu Tyr Leu Ala Phe Trp 145 150 155 160 Leu Asn Glu Pro His Phe Val Gly Ser Ala Tyr Val Pro Glu Ser Val 165 170 175 Gly Ser Phe Thr Gly Asp Asp Asp Lys Val Tyr Phe Phe Phe Arg Glu 180 185 190 Arg Ala Val Glu Ser Asp Cys Tyr Ala Glu Gln Val Val Ala Arg Val 195 200 205 Ala Arg Val Cys Lys Gly Asp Met Gly Gly Ala Arg Thr Leu Gln Arg 210 215 220 Lys Trp Thr Thr Phe Leu Lys Ala Arg Leu Ala Cys Ser Ala Pro Asn 225 230 235 240 Trp Gln Leu Tyr Phe Asn Gln Leu Gln Ala Met His Thr Leu Gln Asp 245 250 255 Thr Ser Trp His Asn Thr Thr Phe Phe Gly Val Phe Gln Ala Gln Trp 260 265 270 Gly Asp Met Tyr Leu Ser Ala Ile Cys Glu Tyr Gln Leu Glu Glu Ile 275 280 285 Gln Arg Val Phe Glu Gly Pro Tyr Lys Glu Tyr His Glu Glu Ala Gln 290 295 300 Lys Trp Asp Arg Tyr Thr Asp Pro Val Pro Ser Pro Arg Pro Gly Ser 305 310 315 320 Cys Ile Asn Asn Trp His Arg Arg His Gly Tyr Thr Ser Ser Leu Glu 325 330 335 Leu Pro Asp Asn Ile Leu Asn Phe Val Lys Lys His Pro Leu Met Glu 340 345 350 Glu Gln Val Gly Pro Arg Trp Ser Arg Pro Leu Leu Val Lys Lys Gly 355 360 365 Thr Asn Phe Thr His Leu Val Ala Asp Arg Val Thr Gly Leu Asp Gly 370 375 380 Ala Thr Tyr Thr Val Leu Phe Ile Gly Thr Gly Asp Gly Trp Leu Leu 385 390 395 400 Lys Ala Val Ser Leu Gly Pro Trp Val His Leu Ile Glu Glu Leu Gln 405 410 415 Leu Phe Asp Gln Glu Pro Met Arg Ser Leu Val Leu Ser Gln Ser Lys 420 425 430 Val Lys Leu Leu Phe Ala Gly Ser Arg Ser Gln Leu Val Gln Leu Pro 435 440 445 Val Ala Asp Cys Met Lys Tyr Arg Ser Cys Ala Asp Cys Val Leu Ala 450 455 460 Arg Asp Pro Tyr Cys Ala Trp Ser Val Asn Thr Ser Arg Cys Val Ala 465 470 475 480 Val Gly Gly His Ser Gly Ser Leu Leu Ile Gln His Val Met Thr Ser 485 490 495 Asp Thr Ser Gly Ile Cys Asn Leu Arg Gly Ser Lys Lys Val Arg Pro 500 505 510 Thr Pro Lys Asn Ile Thr Val Val Ala Gly Thr Asp Leu Val Leu Pro 515 520 525 Cys His Leu Ser Ser Asn Leu Ala His Ala Arg Trp Thr Phe Gly Gly 530 535 540 Arg Asp Leu Pro Ala Glu Gln Pro Gly Ser Phe Leu Tyr Asp Ala Arg 545 550 555 560 Leu Gln Ala Leu Val Val Met Ala Ala Gln Pro Arg His Ala Gly Ala 565 570 575 Tyr His Cys Phe Ser Glu Glu Gln Gly Ala Arg Leu Ala Ala Glu Gly 580 585 590 Tyr Leu Val Ala Val Val Ala Gly Pro Ser Val Thr Leu Glu Ala Arg 595 600 605 Ala Pro Leu Glu Asn Leu Gly Leu Val Trp Leu Ala Val Val Ala Leu 610 615 620 Gly Ala Val Cys Leu Val Leu Leu Leu Leu Val Leu Ser Leu Arg Arg 625 630 635 640 Arg Leu Arg Glu Glu Leu Glu Lys Gly Ala Lys Ala Thr Glu Arg Thr 645 650 655 Leu Val Tyr Pro Leu Glu Leu Pro Lys Glu Pro Thr Ser Pro Pro Phe 660 665 670 Arg Pro Cys Pro Glu Pro Asp Glu Lys Leu Trp Asp Pro Val Gly Tyr 675 680 685 Tyr Tyr Ser Asp Gly Ser Leu Lys Ile Val Pro Gly His Ala Arg Cys 690 695 700 Gln Pro Gly Gly Gly Pro Pro Ser Pro Pro Pro Gly Ile Pro Gly Gln 705 710 715 720 Pro Leu Pro Ser Pro Thr Arg Leu His Leu Gly Gly Gly Arg Asn Ser 725 730 735 Asn Ala Asn Gly Tyr Val Arg Leu Gln Leu Gly Gly Glu Asp Arg Gly 740 745 750 Gly Leu Gly His Pro Leu Pro Glu Leu Ala Asp Glu Leu Arg Arg Lys 755 760 765 Leu Gln Gln Arg Gln Pro Leu Pro Asp Ser Asn Pro Glu Glu Ser Ser 770 775 780 Val 785 219 66 PRT Homo sapien 219 Met Lys Met Arg Ala Lys Ile Leu His Gln Asn Gly Asn Asp Pro Ile 1 5 10 15 Ser Pro Val Lys Ala Glu Trp Val Glu Trp Gly Leu Arg Val Trp Ile 20 25 30 Gln Cys Phe Glu Leu His Ser Ser Arg Glu Ala Val Gln Lys Gly Gly 35 40 45 Ile Leu Gly Asn Leu Arg Lys Ile Val Gly Glu Thr Ser Phe Leu Leu 50 55 60 Val Ser 65 220 128 PRT Homo sapien 220 Glu Val Glu Gly Arg Ser Ala Cys Met Ala Met Gly Leu Phe Phe Ile 1 5 10 15 Pro Phe Leu Asn Cys Thr Gln Gln Gln Trp Phe Leu Leu Gly Leu Leu 20 25 30 Lys Thr Ala Gly Ile Trp Glu Lys Glu His His Arg Leu Ser Gln His 35 40 45 Gly Asn Ile Asn Leu Ile Pro Glu Lys Gly Arg Ser Pro Gln Arg Tyr 50 55 60 Val Arg Phe Asn Ser Phe Ser Ser Gly Pro Gly Ser Ser Phe Ser Cys 65 70 75 80 Ser Gly Leu Asn Arg Asp Ala Leu Ile Ser Leu Gly Ile Leu Leu Leu 85 90 95 Val Leu Ser Leu Thr Ser Gly Ala Lys Ile Arg Arg Pro Glu Phe Gln 100 105 110 Ile Tyr Ser Val Thr Gln Ser Leu Leu Gln Ser Leu Arg Asp Val Val 115 120 125 221 64 PRT Homo sapien 221 Met Gly Ile Leu Glu Pro Gln Asp Val Arg Ala Gly Arg Asp Ala Ile 1 5 10 15 Pro Val Tyr Thr Arg Gly Asn Ser Ser Arg Leu Trp Glu Gly Arg Arg 20 25 30 Val Leu Val Thr Glu Arg Glu Leu Lys Leu Arg Ile Pro Glu Ser Arg 35 40 45 Ser Cys Leu Pro Ser Ala Ile Phe Leu Pro Ile Asn Leu Cys Tyr Val 50 55 60 222 105 PRT Homo sapien 222 Cys Lys Leu Phe Gly Arg Val Gly Asp Ala Val Ser Phe Cys His Pro 1 5 10 15 Gly Trp Ser Ala Val Ala Arg Ser Gln Leu Thr Ala Thr Ser Ala Leu 20 25 30 Gln Gly Ser Gly Asn Ser Ala Ser Val Ser Ala Val Ala Gly Ile Thr 35 40 45 Gly Met Arg His His Thr Arg Leu Ile Phe Val Phe Leu Val Glu Thr 50 55 60 Arg Phe His His Val Gly Gln Asp Gly Leu Glu Pro Leu Thr Ser Gly 65 70 75 80 Asp Leu Pro Ile Ser Ala Ser Gln Ser Ala Gly Ile Thr Ser Val Ser 85 90 95 His Arg Ala Arg Pro Ala Asn Phe Phe 100 105 223 109 PRT Homo sapien 223 Met Met Trp Leu Ser Val Gly Gly Gly Gly Arg Glu Trp Ser Glu Met 1 5 10 15 Leu Gly Val Val Trp Trp Trp Gly Gly Val Gly Val Trp Val Gly Val 20 25 30 Gly Val Cys Gly Cys Val Trp Trp Val Val Val Gly Val Trp Trp Trp 35 40 45 Arg Cys Val Gly Cys Gly Cys Val Val Trp Trp Gly Gly Val Val Gly 50 55 60 Val Gly Gly Cys Trp Gly Gly Cys Val Cys Val Val Gly Val Cys Val 65 70 75 80 Cys Val Gly Gly Gly Val Val Gly Arg Val Val Gly Gly Ala Gly Val 85 90 95 Cys Gly Gly Arg Cys Gly Cys Cys Val Val Trp Trp Cys 100 105 224 196 PRT Homo sapien 224 Thr Arg Pro Gln Ser His Thr Thr Thr Glu His Pro Pro Pro Pro Pro 1 5 10 15 Thr Thr Ile His Ile Thr Gln Thr Leu His Lys Lys Thr Asn Thr Thr 20 25 30 Asn Thr Gln Gln Lys Lys His Thr Asn Thr Gln Ile Thr Ile Thr Gln 35 40 45 Gln His Thr Pro Gln His Thr Thr Thr Pro Pro Thr Pro His His Ser 50 55 60 Thr Pro Pro His Asn Thr Thr Pro Ala Pro Pro Pro His Thr Pro Ala 65 70 75 80 Pro Pro Thr Thr Arg Pro Thr Thr Pro Pro Pro Thr His Thr His Thr 85 90 95 Pro Thr Thr His Thr His Pro Pro Gln His Pro Pro Thr Pro Thr Thr 100 105 110 Thr Thr Pro Pro His His Ala Pro Thr Pro His Thr Pro Pro Pro Thr 115 120 125 Thr Pro Pro Arg Pro Pro Thr Thr His Thr His Thr Pro Pro His Pro 130 135 140 Pro Thr Pro Pro Pro Leu Pro Thr Thr Thr Pro His Pro Thr Ser His 145 150 155 160 Ser Thr Leu Ser Pro His His Pro His Ser Thr Thr Ser Ser Leu Pro 165 170 175 Ser Thr His Asn Asn Ile Thr Asn Thr Pro Pro Ala His Thr Leu Thr 180 185 190 Pro His Thr Ser 195 225 92 PRT Homo sapien 225 Met Thr Ser Leu Pro Glu Gly Pro Arg Ala Ser Glu Asp Gly Ala Thr 1 5 10 15 Pro Glu Ala Gly Gly Phe Thr Asn Ser Ser His Leu Tyr Arg Arg Pro 20 25 30 Ala Arg Cys Gln Ala Cys Trp Gln Ala Gln Gly Lys Ala His Ser Thr 35 40 45 Ser Arg His Gly Pro Cys Ser His Gly Ala Tyr Ser Leu Ala Arg Gln 50 55 60 Thr Arg Asn Lys Lys Leu Gln Ser Ser Val Glu Val Cys Arg Val Val 65 70 75 80 Gly Tyr Ser Asp Leu Ala Leu Tyr Thr His Phe Ala 85 90 226 42 PRT Homo sapien 226 Met Lys Ile Tyr Gly Ser Val Phe Gln Asn Asp Glu Glu Phe Gln Asp 1 5 10 15 Gly Gly Ser Gly Lys Ile Leu Leu Gln Glu Lys Ser Val Leu Gly Pro 20 25 30 Met Cys Lys His Leu Leu Arg Asn Leu Glu 35 40 227 57 PRT Homo sapien 227 Met Leu Ser Gln Arg Tyr Arg Lys Val Leu Leu Gly Pro Ser Val Thr 1 5 10 15 Leu Ser Phe His Ile Pro Thr Leu His Arg Pro Ser Leu Gln Leu Pro 20 25 30 Ala Pro Ala Pro His Cys Arg Ser Pro Gly Phe Cys Leu Glu Leu Asn 35 40 45 Glu Glu Met Gly Pro Leu Ala Leu Ala 50 55 228 205 PRT Homo sapien 228 Gln Gln Gly Lys Leu Val Ala Asp Ser Ala Lys His Leu Gly Leu Lys 1 5 10 15 His Val Val Tyr Ser Gly Leu Glu Asn Val Lys Arg Leu Thr Asp Gly 20 25 30 Lys Leu Glu Val Pro His Phe Asp Ser Lys Gly Glu Val Glu Glu Tyr 35 40 45 Phe Trp Ser Ile Gly Ile Pro Met Thr Ser Val Arg Val Ala Ala Tyr 50 55 60 Phe Glu Asn Phe Leu Ala Ala Trp Arg Pro Val Lys Ala Ser Asp Gly 65 70 75 80 Asp Tyr Tyr Thr Leu Ala Val Pro Met Gly Asp Val Pro Met Asp Gly 85 90 95 Ile Ser Val Ala Asp Ile Gly Ala Ala Val Ser Ser Ile Phe Asn Ser 100 105 110 Pro Glu Glu Phe Leu Gly Lys Ala Val Gly Leu Ser Ala Glu Ala Leu 115 120 125 Thr Ile Gln Gln Tyr Ala Asp Val Leu Ser Lys Ala Leu Gly Lys Glu 130 135 140 Val Arg Asp Ala Lys Ile Thr Pro Glu Ala Phe Glu Lys Leu Gly Phe 145 150 155 160 Pro Ala Ala Lys Glu Ile Ala Asn Met Cys Arg Phe Tyr Glu Met Lys 165 170 175 Pro Asp Arg Asp Val Asn Leu Thr His Gln Leu Asn Pro Lys Val Lys 180 185 190 Ser Phe Ser Gln Phe Ile Ser Glu Asn Gln Gly Ala Phe 195 200 205 229 46 PRT Homo sapien 229 Met Lys Lys Lys Val Leu Ser Ile Ile Cys Ile Ile Gly Ile His Met 1 5 10 15 Ser Leu His Lys Met Phe Asn Leu Lys Glu Ile Pro Leu Ile Leu Tyr 20 25 30 Val Leu Leu Ser Val Val Cys Phe Ser Phe Leu Ile Leu Ser 35 40 45 230 53 PRT Homo sapien 230 Val Ala Gln Ala Gly Val Gln Trp Arg Asn Ala Asn Ser Leu Gln Pro 1 5 10 15 Ala Pro Ser Trp Leu Lys Gln Ala Leu His Leu Ser Pro Leu Ser Ser 20 25 30 Ala His Tyr Arg His Thr Pro Pro His Pro Ala Asn Phe Phe Glu Phe 35 40 45 Leu Glu Thr Gly Phe 50 231 30 PRT Homo sapien 231 Met Gly Gln Val Gly Val Arg Gly Pro Gly Glu Val Arg Ala Leu Ser 1 5 10 15 Ser Lys Leu Ser Tyr Cys His Val Phe Val Pro Arg Arg Asp 20 25 30 232 39 PRT Homo sapien 232 Met Val Phe Leu Gly Glu Leu Lys Thr Phe Ser Leu Val Ser Val Asn 1 5 10 15 Gln Arg Ala Phe Ser Leu Phe Leu Leu Leu Ile Pro Ser Ser Pro Val 20 25 30 Asn Tyr Phe Ser Phe His Trp 35 233 107 PRT Homo sapien 233 Phe Phe Phe Phe Leu Leu Leu Phe Cys Asp Ser Leu Ala Leu Ser Pro 1 5 10 15 Arg Leu Gln Cys Ser Gly Thr Ile Ser Ala His Cys Asn Leu Cys Leu 20 25 30 Leu Gly Ser Ser Asn Ser Pro Val Ser Ala Ser Trp Val Ala Gly Thr 35 40 45 Thr Gly Ala Cys His His Ala Trp Leu Thr Phe Val Phe Leu Val Glu 50 55 60 Thr Gly Phe His His Val Gly Gln Ala Gly Leu Glu Phe Leu Thr Ser 65 70 75 80 Gly Asp Pro Pro Ala Leu Ala Ser Gln Ser Ala Glu Ile Thr Gly Val 85 90 95 Ser His Arg Ala Trp Pro Val Cys Phe Phe Asn 100 105 234 57 PRT Homo sapien 234 Met Cys Ile Ile Leu Ser Ala His Ala Val Leu Gln Ala Ser Val Pro 1 5 10 15 Leu Ala Val His Val Ser Pro His Ala Arg Ala Gly Pro Ser Trp Ser 20 25 30 Ala Leu Val Ser Lys Trp Val Tyr Ala Glu Ala Asp Phe Gln Ser Val 35 40 45 Ser Cys Pro Pro Ile Gln His Ser Arg 50 55 235 50 PRT Homo sapien 235 Met Lys Val Pro Ala Tyr Ile Asn His Leu Ala Arg Trp Trp Glu Ile 1 5 10 15 Leu Cys Ser Ser Asn Val Leu Leu Val Leu Gly Arg Asp Gly Ala His 20 25 30 Ser Gly Ala Lys Glu Asp Lys Lys Ser Met Gln Asn Leu Ser Leu Leu 35 40 45 Met Ala 50 236 44 PRT Homo sapien 236 Met His Asn Trp Asp Cys Trp Asn Gly Pro Arg His Thr Thr Ala Gly 1 5 10 15 His Cys His Gln Glu Gly Ala Cys Val Leu Glu Gly Ser Gly Gln His 20 25 30 Arg Leu Ala Asn Leu Glu Gly Ser Gln Arg Asp Ser 35 40 237 146 PRT Homo sapien 237 Met Gly Ala Arg Val Pro His Ala Ala Asp Gly Pro Ser Gln Val Glu 1 5 10 15 Leu Pro Gly Val Gln Ser Gly Ser Pro Leu Ala Asp Leu Met Leu Ser 20 25 30 Asp Arg Trp Asp Lys Phe Phe Cys His Ser Ala Gly Leu Cys Pro Glu 35 40 45 Ala Ser Leu Leu Ala Gly Cys Ala His Ala Trp Glu Lys Ala Trp Ala 50 55 60 Val Asn Tyr Gly His Thr Cys Ser Leu Cys Gly His Cys Ser Pro Ala 65 70 75 80 Pro Ile Pro Ile Pro Pro His Pro Thr His Pro Asn Thr His Thr Pro 85 90 95 Arg Pro Gln Thr Pro Thr Pro Thr Thr Pro His Pro Pro Thr Pro Thr 100 105 110 Pro Pro His Pro Pro Gln His Pro His Pro Arg Pro Pro Pro Thr Ser 115 120 125 Thr His Pro Pro Thr His Asn Thr Pro His Thr Thr His His Gln His 130 135 140 His His 145 238 47 PRT Homo sapien 238 Met Tyr Arg Gln Tyr Gly Pro Trp Cys Thr Asn Ala Ala Ser Gly Arg 1 5 10 15 Arg Asp Val Met Asp Gly Arg Gly Arg Gly Thr Phe Asn Pro Ser Ser 20 25 30 Pro Phe Pro Pro Ser Gly Ala Ser Tyr Glu Ile Ser Val His Phe 35 40 45 239 91 PRT Homo sapien 239 Met Val Lys Ile Ser Phe Gln Pro Ala Val Ala Gly Ile Lys Gly Asp 1 5 10 15 Lys Ala Asp Lys Ala Ser Ala Ser Ala Pro Ala Pro Ala Ser Ala Thr 20 25 30 Glu Ile Leu Leu Thr Pro Ala Arg Glu Glu Gln Pro Pro Gln His Arg 35 40 45 Ser Lys Arg Gly Gly Ser Val Gly Gly Val Cys Tyr Leu Ser Met Gly 50 55 60 Met Val Val Leu Leu Met Gly Leu Val Phe Ala Ser Val Tyr Ile Tyr 65 70 75 80 Arg Tyr Phe Phe Leu Ala Gln Leu Ala Arg Asp 85 90 240 188 PRT Homo sapien 240 Met Arg Leu Val Gly Gly Val Gly Ser Phe Arg Leu Gly Gly Val Gly 1 5 10 15 Cys Gly Gly Gly Gly Gly Gly Ala Gly Ala Gly Ser Trp Val Trp Met 20 25 30 Gly Gly Trp Gly Gly Gly Ala Gly Ala Leu Trp Val Ala Val Val Gly 35 40 45 Gly Ala Arg Trp Trp Gly Gly Ala Gly Trp Gly Ser Cys Gly Arg Val 50 55 60 Leu Val Gly Gly Arg Ala Val Val Val Gly Arg Val Gly Val Val Gly 65 70 75 80 Trp Gly Trp Trp Arg Val Val Val Ala Gly Cys Val Cys Gly Gly Gly 85 90 95 Trp Arg Trp Trp Arg Ala Gly Val Gly Gly Gly Gly Gly Ala Val Ser 100 105 110 Gly Pro Ser Gly Ala Gly Pro Gly Arg Arg Cys Ser Met Val Glu Arg 115 120 125 Arg Arg Gly His Val Gly Ser Gly Gly Trp Ala Gly Arg Pro Gly Val 130 135 140 Val Gly Val Trp Ala Arg Cys Val Leu Val Ala Gly Ala Val Trp Arg 145 150 155 160 Arg Gly Gly Ala Val Trp Glu Trp Arg Gly Leu Gly Cys Gly Ala Trp 165 170 175 Cys Val Gly Arg Ser Trp Gly Glu Cys Gly Gly Arg 180 185 241 110 PRT Homo sapien 241 Met Lys Leu Thr Leu Ser Glu Val Lys Met Glu Val Ile Gly Val Pro 1 5 10 15 Trp Arg Asn Gly Ser His Cys Phe Ile Ser Ile Thr Pro Gln Leu Lys 20 25 30 Phe Thr Pro Val Ser Gly His Lys Asn Met Arg Lys Glu Pro Cys Cys 35 40 45 Phe His Lys Gly Asn His Ser Ser Leu Ser Pro Leu Leu Ile Asn Leu 50 55 60 Lys Ser Trp Thr Pro Ser Phe Leu His Trp Pro Arg Pro Thr Leu Thr 65 70 75 80 His Leu Glu Pro Leu Phe Arg Ala Glu Trp His Glu Tyr Val Tyr Leu 85 90 95 Gly Arg Asp Gln Ser Ile Thr Gln Arg Arg Leu Glu Gln His 100 105 110 242 102 PRT Homo sapien 242 Met Pro Ser Leu Pro Thr Arg Ser Leu Leu Ser Pro Cys Val Leu Glu 1 5 10 15 Leu Glu Glu Leu Thr Cys Ala Leu Cys Thr Trp Ala Phe Leu Leu Leu 20 25 30 Cys Leu Ala Leu Val Ala Asp Cys Pro Gly Leu Arg Gln Val Ile Pro 35 40 45 Gly Lys Gln Val Phe Val Leu Phe Ser Met Ser Gly Gly Arg Phe Ile 50 55 60 Leu Leu Ser Val Ser Ser His Phe Pro Ile Pro Phe Lys Lys Leu Trp 65 70 75 80 Pro Ala Gln Gly Arg Ala Leu Ser Cys Cys Ile Thr Ala Glu Pro Thr 85 90 95 Cys Pro His Ala Leu Leu 100 243 86 PRT Homo sapien 243 Leu Ala Val Ser Leu Cys His Gln Ala Gly Val Gln Trp Cys Asn Pro 1 5 10 15 Gly Ser Leu Gln Pro Pro Pro Pro Gly Phe Lys Arg Phe Phe Cys Leu 20 25 30 Cys Leu Pro Ser Ser Trp Gly Tyr Arg His Thr Pro Pro Arg Pro Ala 35 40 45 Asn Phe Cys Val Phe Gly Arg Asp Gly Val Ser Pro Cys Trp Pro Gly 50 55 60 Trp Ser Leu Ser Leu Asp Val Ile Cys Asp Pro Pro Arg Gln Pro Pro 65 70 75 80 Lys Val Leu Gly Leu Gln 85 244 53 PRT Homo sapien 244 Met Leu Leu Pro Phe Ala Val Arg Gly Leu Leu Thr Met Ala Arg Gly 1 5 10 15 Asp Val Ser Glu Ile Gln Val Val Val Ala Ser Trp Ser Thr Gln Leu 20 25 30 Ala His Met Gln Glu Glu Gly Leu Trp Pro Leu Ser Arg Ala Gly Gly 35 40 45 Leu Leu Pro Gln Ala 50 245 183 PRT Homo sapien 245 Leu Thr Pro Ala Gly Val Pro Trp Cys His Leu Gly Ser Leu Gln Pro 1 5 10 15 Leu Pro Pro Arg Phe Lys Ala Val Phe Ser Arg Leu Ala Pro Ser Leu 20 25 30 Glu Tyr Ala Trp Asp Tyr Arg Ala Pro Thr Ser His Ala Arg Leu Ile 35 40 45 Ser Leu Ala Phe Leu Val Glu Thr Gly Phe Ser Pro Thr Val Ala Arg 50 55 60 Leu Val Ser Asn Ser Trp Pro Pro Val Val Arg Pro Pro Leu Pro Ser 65 70 75 80 Gln Ser Ala Gly Ile Thr Gly Val Gly Pro Pro Cys Leu Ala Arg Pro 85 90 95 Ile Leu Pro Pro His Pro Phe Phe Phe Phe Phe Asp Met Glu Ser His 100 105 110 Ala Ile Thr Gln Ala Gly Val Gln Trp Arg His Leu Gly Ser Leu Gln 115 120 125 Pro Pro Pro Pro Met Phe Lys Ala Ser Ser Cys Leu Ser Leu Leu Ser 130 135 140 Ser Trp Asp Tyr Arg Arg Pro Pro Pro Arg Pro Ala Ile Phe Cys Ile 145 150 155 160 Phe Ser Arg Asp Gly Val Ser Pro Cys Ala Pro Gly Trp Ser Arg Ser 165 170 175 Pro Asp Leu Thr Pro Asp Leu 180 246 12 PRT Homo sapien 246 Met Ala Pro Asp Thr Asn Thr Phe Leu His Pro Phe 1 5 10 247 240 PRT Homo sapien 247 Met Gly Asn Cys Gln Ala Gly His Asn Leu His Leu Cys Leu Ala His 1 5 10 15 His Pro Pro Leu Val Cys Ala Thr Leu Ile Leu Leu Leu Leu Gly Leu 20 25 30 Ser Gly Leu Gly Leu Gly Ser Phe Leu Leu Thr His Arg Thr Gly Leu 35 40 45 Arg Ser Pro Asp Ile Pro Gln Asp Trp Val Ser Phe Leu Arg Ser Phe 50 55 60 Gly Gln Leu Thr Leu Cys Pro Arg Asn Gly Thr Val Thr Gly Lys Trp 65 70 75 80 Arg Gly Ser His Val Val Gly Leu Leu Thr Thr Leu Asn Phe Gly Asp 85 90 95 Gly Pro Asp Arg Asn Lys Thr Arg Thr Phe Gln Ala Thr Val Leu Gly 100 105 110 Ser Gln Met Gly Leu Lys Gly Ser Ser Ala Gly Gln Leu Val Leu Ile 115 120 125 Thr Ala Arg Val Thr Thr Glu Arg Thr Ala Gly Thr Cys Leu Tyr Phe 130 135 140 Ser Ala Val Pro Gly Ile Leu Pro Ser Ser Gln Pro Pro Ile Ser Cys 145 150 155 160 Ser Glu Glu Gly Ala Gly Asn Ala Thr Leu Ser Pro Arg Met Gly Glu 165 170 175 Glu Cys Val Ser Val Trp Ser His Glu Gly Leu Val Leu Thr Lys Leu 180 185 190 Leu Thr Ser Glu Glu Leu Ala Leu Cys Gly Ser Arg Leu Leu Val Leu 195 200 205 Gly Ser Phe Leu Leu Leu Phe Cys Gly Leu Leu Cys Cys Val Thr Ala 210 215 220 Met Cys Phe His Pro Arg Arg Glu Ser His Trp Ser Arg Thr Arg Leu 225 230 235 240 248 75 PRT Homo sapien 248 Met Arg Arg Ala Val Ala Ser Val Met Tyr Arg Trp Ser Arg Pro Arg 1 5 10 15 Tyr Thr Gln Glu Ala Arg Arg Tyr Phe Phe Phe Ser Glu Leu Ser Pro 20 25 30 Gly Ser Lys Gly Glu Ala Met Gly Asp Pro Gly Met Val Leu Ala Ser 35 40 45 Gly Gly Cys Phe Leu Val Thr Gly Val Ser Ser Lys Gln Asn Gly Ile 50 55 60 Arg Met Lys Arg Gly Lys Gly Met Gly His Lys 65 70 75 249 594 PRT Homo sapien 249 Val Pro Gly Arg Lys Leu His Arg Ser Arg Leu Gln Ala Ala Ala Pro 1 5 10 15 Arg Pro Ser Thr Cys Ala Gln Ser Leu Cys Trp Ser Arg Pro Pro Ala 20 25 30 Ala Gly Thr Gly Thr Gly Asp Pro Ser Gln Ser Lys Ala Pro Thr Met 35 40 45 Ala Met Gly Leu Phe Arg Val Cys Leu Val Val Val Thr Ala Ile Ile 50 55 60 Asn His Pro Leu Leu Phe Pro Arg Glu Asn Ala Thr Val Pro Glu Asn 65 70 75 80 Glu Glu Glu Ile Ile Arg Lys Met Gln Ala His Gln Glu Lys Leu Gln 85 90 95 Leu Glu Gln Leu Arg Leu Glu Glu Glu Val Ala Arg Leu Ala Ala Glu 100 105 110 Lys Glu Ala Leu Glu Gln Val Ala Glu Glu Gly Arg Gln Gln Asn Glu 115 120 125 Thr Arg Val Ala Trp Asp Leu Trp Ser Thr Leu Cys Met Ile Leu Phe 130 135 140 Leu Met Ile Glu Val Trp Arg Gln Asp His Gln Glu Gly Pro Ser Pro 145 150 155 160 Glu Cys Leu Gly Gly Glu Glu Asp Glu Leu Pro Gly Leu Gly Gly Ala 165 170 175 Pro Leu Gln Gly Leu Thr Leu Pro Asn Lys Ala Thr Leu Gly His Phe 180 185 190 Tyr Glu Arg Cys Ile Arg Gly Ala Thr Ala Asp Ala Ala Arg Thr Arg 195 200 205 Glu Phe Leu Glu Gly Phe Val Asp Asp Leu Leu Glu Ala Leu Arg Ser 210 215 220 Leu Cys Asn Arg Asp Thr Asp Met Glu Val Glu Asp Phe Ile Gly Val 225 230 235 240 Asp Ser Met Tyr Glu Asn Trp Gln Val Asp Arg Pro Leu Leu Cys His 245 250 255 Leu Phe Val Pro Phe Thr Pro Pro Glu Pro Tyr Arg Phe His Pro Glu 260 265 270 Leu Trp Cys Ser Gly Arg Ser Val Pro Leu Asp Arg Gln Gly Tyr Gly 275 280 285 Gln Ile Lys Val Val Arg Ala Asp Gly Asp Thr Leu Ser Cys Ile Cys 290 295 300 Gly Lys Thr Lys Leu Gly Glu Asp Met Leu Cys Leu Leu His Gly Arg 305 310 315 320 Asn Ser Met Ala Pro Pro Cys Gly Asp Met Glu Asn Leu Leu Cys Ala 325 330 335 Thr Asp Ser Leu Tyr Leu Asp Thr Met Gln Val Met Lys Trp Phe Gln 340 345 350 Thr Ala Leu Thr Arg Ala Trp Lys Gly Ile Ala His Lys Tyr Glu Phe 355 360 365 Asp Leu Ala Phe Gly Gln Leu Asp Ser Pro Gly Ser Leu Lys Ile Lys 370 375 380 Phe Arg Ser Gly Lys Phe Met Pro Phe Asn Leu Ile Pro Val Ile Gln 385 390 395 400 Cys Asp Asp Ser Asp Leu Tyr Phe Val Ser His Leu Pro Arg Glu Pro 405 410 415 Ser Glu Gly Thr Pro Ala Ser Ser Thr Asp Trp Leu Leu Ser Phe Ala 420 425 430 Val Tyr Glu Arg His Phe Leu Arg Thr Thr Leu Lys Ala Leu Pro Glu 435 440 445 Gly Ala Cys His Leu Ser Cys Leu Gln Ile Ala Ser Phe Leu Leu Ser 450 455 460 Lys Gln Ser Arg Leu Thr Gly Pro Ser Gly Leu Ser Ser Tyr His Leu 465 470 475 480 Lys Thr Ala Leu Leu His Leu Leu Leu Leu Arg Gln Ala Ala Asp Trp 485 490 495 Lys Ala Gly Gln Leu Asp Ala Arg Leu His Glu Leu Leu Cys Phe Leu 500 505 510 Glu Lys Ser Leu Leu Gln Lys Lys Leu His His Phe Phe Ile Gly Asn 515 520 525 Arg Lys Val Pro Glu Ala Met Gly Leu Pro Glu Ala Val Leu Arg Ala 530 535 540 Glu Pro Leu Asn Leu Phe Arg Pro Phe Val Leu Gln Arg Ser Leu Tyr 545 550 555 560 Arg Lys Thr Leu Asp Ser Phe Tyr Glu Met Leu Lys Asn Ala Pro Ala 565 570 575 Leu Ile Ser Glu Tyr Ser Leu His Val Pro Ser Asp Gln Pro Thr Pro 580 585 590 Lys Ser 250 23 PRT Homo sapien 250 Met Tyr Cys Ile Gly Gly Trp Ala Gly Pro Thr Leu Cys Tyr Val Lys 1 5 10 15 Glu Leu Val Leu Val Leu Gly 20 251 213 PRT Homo sapien 251 Ser Pro His Gln Ala Ala Ala Pro Val Asp Gln Thr Pro Arg Thr Leu 1 5 10 15 Ala Thr Met Gly Gln Arg Ala Leu Pro Ser Ser Leu Ala Leu Leu Ser 20 25 30 Arg Pro Leu Ser Pro Pro Pro Ala Ala Cys Ser Gly Asp Pro Gly Cys 35 40 45 Gly Ser Gly Ala Gly Leu Pro Ser Ala Ser Ala Ala Ala Gly Ile Ala 50 55 60 Ser Ser Ala Val Glu Ala Val Cys Gly Asp Ala Ala Pro Ala Cys Leu 65 70 75 80 Leu Arg Thr Pro Leu Arg Gly Leu Leu Lys Pro Thr Gly Pro Arg Ser 85 90 95 Thr Met Glu Cys Pro Pro Ala Leu Ile Val His Pro Pro Thr Gly Gly 100 105 110 Met Ala Arg Arg Ala Ala Ser Gln Pro Trp Ala Ala Ala Ser Ala Thr 115 120 125 Pro Met Leu Ser Ser Lys Ala Ser Leu Cys Ile Pro Thr Glu Arg Pro 130 135 140 Pro Pro Gln Pro Leu Met Arg Thr Pro Ala Ala Arg Ser His Trp Pro 145 150 155 160 Ile Pro His Pro Ala Ser Thr Ala Cys Pro Ala Pro Leu Pro Val Val 165 170 175 Leu Val Ala Pro Arg Ser Thr Ile Leu Ser Met Ser Arg Thr Trp Thr 180 185 190 Cys Arg Arg Trp Ala Val Ala Pro Cys Arg Ala Glu Lys Leu Met Cys 195 200 205 Ser Ser Ser Arg Ser 210 252 32 PRT Homo sapien 252 Met His Glu Leu Thr Ala Arg Leu Thr Gln Pro Leu Asn Ser Gly Ser 1 5 10 15 Cys Phe Ser Leu Ala Ala Ile His His Met Arg Arg Arg Ser Met His 20 25 30 253 58 PRT Homo sapien 253 Met Ser Leu Gln Leu Gln Ile Leu Asn Val Ser Pro Val Ile Trp His 1 5 10 15 Phe Arg His Ser Tyr Leu Lys Pro Gln Phe Ser Leu Pro Val Lys Trp 20 25 30 Gly Ile Ile Ile Pro Ile Leu Pro Arg Leu Leu Lys Gly Leu Ser Glu 35 40 45 Leu Ile Cys Lys Met Leu Asn Arg Thr Gln 50 55 254 34 PRT Homo sapien 254 Met Gly Ser Ala Phe Val Leu Leu Ser Trp Arg Ala Cys Leu Cys Cys 1 5 10 15 Arg Ala Val Ser Val Val Gly Ile Ala Leu Leu Phe Pro Ala Thr Gly 20 25 30 Gln Ile 255 74 PRT Homo sapien 255 Lys Arg Phe Phe Phe Phe Pro Ala Pro Ile Phe Cys Lys Thr Glu Val 1 5 10 15 Pro Glu His Arg Arg Ser Ser Ser Gln Ala Asn Phe Ile Lys Lys Lys 20 25 30 Leu Glu Val Cys Phe Asp Phe Ala Val Ile Cys Phe Ile Thr Ser Ile 35 40 45 Phe Gly Glu Gln Pro Gln Leu Leu Ile Phe Met Glu Lys Tyr Phe Gln 50 55 60 Val Gln Gly Gln Tyr Ile Ser Gln Ser Glu 65 70 256 34 PRT Homo sapien 256 Met Ile Lys Val Cys Val Pro Ile Thr Phe Pro Leu Pro Glu Arg Arg 1 5 10 15 Val Ser Arg Lys Ile Asn Ser Ile Leu Asp Ala Gly Thr Ser Pro Arg 20 25 30 Pro Arg 257 37 PRT Homo sapien 257 Met Asn Ser Ser Asn Arg Arg Leu Phe Trp Lys Lys Ser Gln Gly Leu 1 5 10 15 Ser Pro Ser Trp Val Ala Pro Tyr Lys Ser Asn Ser Ser Ser Gly Ser 20 25 30 Leu Val Tyr Pro Leu 35 258 73 PRT Homo sapien 258 Met Glu Phe Leu Leu Leu Glu Val Glu Lys Tyr Asn Ile Ile Lys Lys 1 5 10 15 Asp Val Ile Pro Thr Arg Gly Leu Arg Gly Lys Leu Lys Asp Ile Lys 20 25 30 Gln Ser Asn Leu Val Ile Val Lys Thr Ile Tyr Val Gly His Arg Thr 35 40 45 Glu Asp Gln Val Ser Lys Glu Asp Gly Ser Val Pro Phe Val Ser Pro 50 55 60 Val Pro Lys Ala Val Phe Gly Ala Ser 65 70 259 1533 PRT Homo sapien 259 Met Tyr Ile Arg Val Ser Tyr Asp Thr Lys Pro Asp Ser Leu Leu His 1 5 10 15 Leu Met Val Lys Asp Trp Gln Leu Glu Leu Pro Lys Leu Leu Ile Ser 20 25 30 Val His Gly Gly Leu Gln Asn Phe Glu Met Gln Pro Lys Leu Lys Gln 35 40 45 Val Phe Gly Lys Gly Leu Ile Lys Ala Ala Met Thr Thr Gly Ala Trp 50 55 60 Ile Phe Thr Gly Gly Val Ser Thr Gly Val Ile Ser His Val Gly Asp 65 70 75 80 Ala Leu Lys Asp His Ser Ser Lys Ser Arg Gly Arg Val Cys Ala Ile 85 90 95 Gly Ile Ala Pro Trp Gly Ile Val Glu Asn Lys Glu Asp Leu Val Gly 100 105 110 Lys Asp Val Thr Arg Val Tyr Gln Thr Met Ser Asn Pro Leu Ser Lys 115 120 125 Leu Ser Val Leu Asn Asn Ser His Thr His Phe Ile Leu Ala Asp Asn 130 135 140 Gly Thr Leu Gly Lys Tyr Gly Ala Glu Val Lys Leu Arg Arg Leu Leu 145 150 155 160 Glu Lys His Ile Ser Leu Gln Lys Ile Asn Thr Arg Leu Gly Gln Gly 165 170 175 Val Pro Leu Val Gly Leu Val Val Glu Gly Gly Pro Asn Val Val Ser 180 185 190 Ile Val Leu Glu Tyr Leu Gln Glu Glu Pro Pro Ile Pro Val Val Ile 195 200 205 Cys Asp Gly Ser Gly Arg Ala Ser Asp Ile Leu Ser Phe Ala His Lys 210 215 220 Tyr Cys Glu Glu Gly Gly Ile Ile Asn Glu Ser Leu Arg Glu Gln Leu 225 230 235 240 Leu Val Thr Ile Gln Lys Thr Phe Asn Tyr Asn Lys Ala Gln Ser His 245 250 255 Gln Leu Phe Ala Ile Ile Met Glu Cys Met Lys Lys Lys Glu Leu Val 260 265 270 Thr Val Phe Arg Met Gly Ser Glu Gly Gln Gln Asp Ile Glu Met Ala 275 280 285 Ile Leu Thr Ala Leu Leu Lys Gly Thr Asn Val Ser Ala Pro Asp Gln 290 295 300 Leu Ser Leu Ala Leu Ala Trp Asn Arg Val Asp Ile Ala Arg Ser Gln 305 310 315 320 Ile Phe Val Phe Gly Pro His Trp Thr Pro Leu Gly Ser Leu Ala Pro 325 330 335 Pro Thr Asp Ser Lys Ala Thr Glu Lys Glu Lys Lys Pro Pro Met Ala 340 345 350 Thr Thr Lys Gly Gly Arg Gly Lys Gly Lys Gly Lys Lys Lys Gly Lys 355 360 365 Val Lys Glu Glu Val Glu Glu Glu Thr Asp Pro Arg Lys Ile Glu Leu 370 375 380 Leu Asn Trp Val Asn Ala Leu Glu Gln Ala Met Leu Asp Ala Leu Val 385 390 395 400 Leu Asp Arg Val Asp Phe Val Lys Leu Leu Ile Glu Asn Gly Val Asn 405 410 415 Met Gln His Phe Leu Thr Ile Pro Arg Leu Glu Glu Leu Tyr Asn Thr 420 425 430 Arg Leu Gly Pro Pro Asn Thr Leu His Leu Leu Val Arg Asp Val Lys 435 440 445 Lys Ser Asn Leu Pro Pro Asp Tyr His Ile Ser Leu Ile Asp Ile Gly 450 455 460 Leu Val Leu Glu Tyr Leu Met Gly Gly Ala Tyr Arg Cys Asn Tyr Thr 465 470 475 480 Arg Lys Asn Phe Arg Thr Leu Tyr Asn Asn Leu Phe Gly Pro Lys Arg 485 490 495 Pro Lys Ala Leu Lys Leu Leu Gly Met Glu Asp Asp Glu Pro Pro Ala 500 505 510 Lys Gly Lys Lys Lys Lys Lys Lys Lys Lys Glu Glu Glu Ile Asp Ile 515 520 525 Asp Val Asp Asp Pro Ala Val Ser Arg Phe Gln Tyr Pro Phe His Glu 530 535 540 Leu Met Val Trp Ala Val Leu Met Lys Arg Gln Lys Met Ala Val Phe 545 550 555 560 Leu Trp Gln Arg Gly Glu Glu Ser Met Ala Lys Ala Leu Val Ala Cys 565 570 575 Lys Leu Tyr Lys Ala Met Ala His Glu Ser Ser Glu Ser Asp Leu Val 580 585 590 Asp Asp Ile Ser Gln Asp Leu Asp Asn Asn Ser Lys Asp Phe Gly Gln 595 600 605 Leu Ala Leu Glu Leu Leu Asp Gln Ser Tyr Lys His Asp Glu Gln Ile 610 615 620 Ala Met Lys Leu Leu Thr Tyr Glu Leu Lys Asn Trp Ser Asn Ser Thr 625 630 635 640 Cys Leu Lys Leu Ala Val Ala Ala Lys His Arg Asp Phe Ile Ala His 645 650 655 Thr Cys Ser Gln Met Leu Leu Thr Asp Met Trp Met Gly Arg Leu Arg 660 665 670 Met Arg Lys Asn Pro Gly Leu Lys Val Ile Met Gly Ile Leu Leu Pro 675 680 685 Pro Thr Ile Leu Phe Leu Glu Phe Arg Thr Tyr Asp Asp Phe Ser Tyr 690 695 700 Gln Thr Ser Lys Glu Asn Glu Asp Gly Lys Glu Lys Glu Glu Glu Asn 705 710 715 720 Thr Asp Ala Asn Ala Asp Ala Gly Ser Arg Lys Gly Asp Glu Glu Asn 725 730 735 Glu His Lys Lys Gln Arg Ser Ile Pro Ile Gly Thr Lys Ile Cys Glu 740 745 750 Phe Tyr Asn Ala Pro Ile Val Lys Phe Trp Phe Tyr Thr Ile Ser Tyr 755 760 765 Leu Gly Tyr Leu Leu Leu Phe Asn Tyr Val Ile Leu Val Arg Met Asp 770 775 780 Gly Trp Pro Ser Leu Gln Glu Trp Ile Val Ile Ser Tyr Ile Val Ser 785 790 795 800 Leu Ala Leu Glu Lys Ile Arg Glu Ile Leu Met Ser Glu Pro Gly Lys 805 810 815 Leu Ser Gln Lys Ile Lys Val Trp Leu Gln Glu Tyr Trp Asn Ile Thr 820 825 830 Asp Leu Val Ala Ile Ser Thr Phe Met Ile Gly Ala Ile Leu Arg Leu 835 840 845 Gln Asn Gln Pro Tyr Met Gly Tyr Gly Arg Val Ile Tyr Cys Val Asp 850 855 860 Ile Ile Phe Trp Tyr Ile Arg Val Leu Asp Ile Phe Gly Val Asn Lys 865 870 875 880 Tyr Leu Gly Pro Tyr Val Met Met Ile Gly Lys Met Met Ile Asp Met 885 890 895 Leu Tyr Phe Val Val Ile Met Leu Val Val Leu Met Ser Phe Gly Val 900 905 910 Ala Arg Gln Ala Ile Leu His Pro Glu Glu Lys Pro Ser Trp Lys Leu 915 920 925 Ala Arg Asn Ile Phe Tyr Met Pro Tyr Trp Met Ile Tyr Gly Glu Val 930 935 940 Phe Ala Asp Gln Ile Asp Leu Tyr Ala Met Glu Ile Asn Pro Pro Cys 945 950 955 960 Gly Glu Asn Leu Tyr Asp Glu Glu Gly Lys Arg Leu Pro Pro Cys Ile 965 970 975 Pro Gly Ala Trp Leu Thr Pro Ala Leu Met Ala Cys Tyr Leu Leu Val 980 985 990 Ala Asn Ile Leu Leu Val Asn Leu Leu Ile Ala Val Phe Asn Asn Thr 995 1000 1005 Phe Phe Glu Val Lys Ser Ile Ser Asn Gln Val Trp Lys Phe Gln 1010 1015 1020 Arg Tyr Gln Leu Ile Met Thr Phe His Asp Arg Pro Val Leu Pro 1025 1030 1035 Pro Pro Met Ile Ile Leu Ser His Ile Tyr Ile Ile Ile Met Arg 1040 1045 1050 Leu Ser Gly Arg Cys Arg Lys Lys Arg Glu Gly Asp Gln Glu Glu 1055 1060 1065 Arg Asp Arg Gly Leu Lys Leu Phe Leu Ser Asp Glu Glu Leu Lys 1070 1075 1080 Arg Leu His Glu Phe Glu Glu Gln Cys Val Gln Glu His Phe Arg 1085 1090 1095 Glu Lys Glu Asp Glu Gln Gln Ser Ser Ser Asp Glu Arg Ile Arg 1100 1105 1110 Val Thr Ser Glu Arg Val Glu Asn Met Ser Met Arg Leu Glu Glu 1115 1120 1125 Ile Asn Glu Arg Glu Thr Phe Met Lys Thr Ser Leu Gln Thr Val 1130 1135 1140 Asp Leu Arg Leu Ala Gln Leu Glu Glu Leu Ser Asn Arg Met Val 1145 1150 1155 Asn Ala Leu Glu Asn Leu Ala Gly Ile Asp Arg Ser Asp Leu Ile 1160 1165 1170 Gln Ala Arg Ser Arg Ala Ser Ser Glu Cys Glu Ala Thr Tyr Leu 1175 1180 1185 Leu Arg Gln Ser Ser Ile Asn Ser Ala Asp Gly Tyr Ser Leu Tyr 1190 1195 1200 Arg Tyr His Phe Asn Gly Glu Glu Leu Leu Phe Glu Asp Thr Ser 1205 1210 1215 Leu Ser Thr Ser Pro Gly Thr Gly Val Arg Lys Lys Thr Cys Ser 1220 1225 1230 Phe Arg Ile Lys Glu Glu Lys Asp Val Lys Thr His Leu Val Pro 1235 1240 1245 Glu Cys Gln Asn Ser Leu His Leu Ser Leu Gly Thr Ser Thr Ser 1250 1255 1260 Ala Thr Pro Asp Gly Ser His Leu Ala Val Asp Asp Leu Lys Asn 1265 1270 1275 Ala Glu Glu Ser Lys Leu Gly Pro Asp Ile Gly Ile Ser Lys Glu 1280 1285 1290 Asp Asp Glu Arg Gln Thr Asp Ser Lys Lys Glu Glu Thr Ile Ser 1295 1300 1305 Pro Ser Leu Asn Lys Thr Asp Val Ile His Gly Gln Asp Lys Ser 1310 1315 1320 Asp Val Gln Asn Thr Gln Leu Thr Val Glu Thr Thr Asn Ile Glu 1325 1330 1335 Gly Thr Ile Ser Tyr Pro Leu Glu Glu Thr Lys Ile Thr Arg Tyr 1340 1345 1350 Phe Pro Asp Glu Thr Ile Asn Ala Cys Lys Thr Met Lys Ser Arg 1355 1360 1365 Ser Phe Val Tyr Ser Arg Gly Arg Lys Leu Val Gly Gly Val Asn 1370 1375 1380 Gln Asp Val Glu Tyr Ser Ser Ile Thr Asp Gln Gln Leu Thr Thr 1385 1390 1395 Glu Trp Gln Cys Gln Val Gln Lys Ile Thr Arg Ser His Ser Thr 1400 1405 1410 Asp Ile Pro Tyr Ile Val Ser Glu Ala Ala Val Gln Ala Glu Gln 1415 1420 1425 Lys Glu Gln Phe Ala Asp Met Gln Asp Glu His His Val Ala Glu 1430 1435 1440 Ala Ile Pro Arg Ile Pro Arg Leu Ser Leu Thr Ile Thr Asp Arg 1445 1450 1455 Asn Gly Met Glu Asn Leu Leu Ser Val Lys Pro Asp Gln Thr Leu 1460 1465 1470 Gly Phe Pro Ser Leu Arg Ser Lys Ser Leu His Gly His Pro Arg 1475 1480 1485 Asn Val Lys Ser Ile Gln Gly Lys Leu Asp Arg Ser Gly His Ala 1490 1495 1500 Ser Ser Val Ser Ser Leu Val Ile Val Ser Gly Met Thr Ala Glu 1505 1510 1515 Glu Lys Lys Val Lys Lys Glu Lys Ala Ser Thr Glu Thr Glu Cys 1520 1525 1530 260 92 PRT Homo sapien 260 Met Ile Ile Leu Val Val Gly Arg Ile Thr Arg Gly Asn Ala Leu Tyr 1 5 10 15 Ser Gln Glu Glu Cys Cys Val Cys Thr Thr Gln Leu Thr Thr Trp Val 20 25 30 Val Cys Ser Thr Leu His Cys Val Ser Ile Leu Trp Ser Val Arg Pro 35 40 45 Ser Leu Ser Glu Gly Gly Tyr Leu Pro Leu Ala Ala Ser Val Ser Ala 50 55 60 Ala Ile Val Val Cys Phe Val Cys Val Cys Val Val Ser Cys His Asp 65 70 75 80 Ala Thr Ile Leu Leu Arg Ile Gly Asn Phe Gly Gly 85 90 261 66 PRT Homo sapien 261 Met Glu Leu Leu Thr Asp Lys Gly Glu Ile Leu Asp Leu Glu Pro Phe 1 5 10 15 Pro Ala Ile Leu Leu Phe Ser Leu Cys Leu Gly Ser Trp Phe His Ser 20 25 30 Ala Arg His Glu Gly Pro Phe Gln Phe Asp Asp Ile Arg Leu Leu Thr 35 40 45 Leu Ser Trp Met Pro Cys Cys Leu Gln Gln His Asp Phe Thr Val Cys 50 55 60 Phe Ser 65 262 90 PRT Homo sapien 262 Met Trp Asn Ile Pro Gly Leu Ala Gly Ala Met Pro Ala Met Gln Thr 1 5 10 15 Ser Pro Glu Pro Ser His Pro Gly Ser Val Arg Val Pro Arg Ala Val 20 25 30 Ala Pro His Pro Pro Pro Thr Gly Pro Cys Ser Trp Ser Cys Cys Asp 35 40 45 Ser Phe Ile Ile Pro Trp Ala Gly Val Gly Leu Ser Leu Cys Phe Cys 50 55 60 Leu Leu Phe Lys Glu Asp Glu Val Ser Met Glu Asn Lys Thr Asn Val 65 70 75 80 Val Thr Pro Ser Leu Arg Arg Val His Cys 85 90 263 13 PRT Homo sapien 263 Met Ser Gly Gln Pro Arg Pro Thr Ser Pro Cys Val Leu 1 5 10 264 100 PRT Homo sapien 264 Phe Phe Leu Arg Trp Ser Leu Ala Gln Val Ala Gln Ala Ala Arg Gln 1 5 10 15 Trp Leu Asn Leu Ser Ser Leu Gln Pro Pro Pro Pro Gly Phe Lys Arg 20 25 30 Phe Ser Cys Leu Gly Leu Leu Ser Ser Trp Asp Tyr Arg His Ala Pro 35 40 45 Pro Arg Pro Ala Ile Phe Val Phe Leu Val Glu Met Gly Phe His His 50 55 60 Ile Val Gln Ala Gly Leu Lys Pro Leu Thr Ser Gly Asp Leu Ala Thr 65 70 75 80 Ser Ala Phe Gln Ser Ala Glu Ile Ile Gly Val Ser His Cys Ala Gln 85 90 95 Pro Gln Lys Ser 100 265 10 PRT Homo sapien 265 Met Lys Gly Lys Ile Leu Ile Phe Pro Ile 1 5 10 266 43 PRT Homo sapien 266 Met Ser Pro Glu Pro Ser His Phe Ser Pro Pro Ala Pro Pro Ser Phe 1 5 10 15 Ser Pro Thr His Pro Ser Leu Pro Leu Thr Trp Ile Ser Ala Pro Ala 20 25 30 Ala Ser Pro Leu Pro Leu Leu Leu Pro Thr Phe 35 40 267 124 PRT Homo sapien 267 Met Val Phe Tyr Cys Ile Leu Phe Leu Gln Leu Ile Gln Phe Cys Met 1 5 10 15 Ser Phe Leu Ser Phe Leu Gly Glu Asn Ile Leu Cys Gln Leu Phe Ser 20 25 30 Thr Val Leu His Tyr Ile Leu Lys Gln Gly Cys Gln Leu Glu Thr Gln 35 40 45 Pro Ser Asp Tyr Lys Ala Gln Asn Val Thr Phe Asn Cys Ala Pro Pro 50 55 60 Gly Gly Leu Ala Leu Gly Lys Asp Gly Glu Arg Asn Ile Leu Arg Tyr 65 70 75 80 Glu His Phe Leu Phe Cys Leu Gln Cys Cys Asp Leu Val Gln Gln Leu 85 90 95 Gln Asn Cys Ser His Leu Asn Arg Cys Ser Phe Ser Phe Phe Thr Leu 100 105 110 Leu Tyr Lys Arg Leu Val Ser Gln Leu His Tyr His 115 120 268 67 PRT Homo sapien 268 Met Pro Glu Phe His Pro His Ser Leu Glu Leu Phe Thr Tyr Ser Pro 1 5 10 15 Ser Gln Glu Leu Leu Asp Glu His Gln Glu Met Arg Phe Lys Tyr Asn 20 25 30 Thr Glu Lys Cys Ala Gln Ala Gly Tyr His Pro Cys Trp Asn Leu Ala 35 40 45 Leu Ala Asn Trp Ala Thr Arg Val Pro Ala Arg Ala Asp Pro Ser Gln 50 55 60 Ser Ala Gly 65 269 23 PRT Homo sapien 269 Met Thr Asp Leu Lys Glu Asn Ser Lys Ala Asp Leu Glu Asn Leu Leu 1 5 10 15 Leu Phe Leu Ser Pro Asn Pro 20 270 46 PRT Homo sapien 270 Met Glu Asn Leu Ser Ser Ile Ser Glu Val Val Asn Ala Ile Ser Gly 1 5 10 15 Ile Gln Arg Leu Ala Val Lys Ser Ser Leu Gly Ser Leu Tyr Leu Thr 20 25 30 Phe Phe Leu Val Ser Ile Leu Lys Met Gln Ser His Ile Leu 35 40 45 271 15 PRT Homo sapien 271 Met Thr Glu Glu Gly Glu Ser Leu Ser Gly Gln Ser Leu Gly Trp 1 5 10 15 272 46 PRT Homo sapien 272 Met Pro Ser Ala Arg Met Ser Asp Gly Leu Val Ala Ala Glu Val Gln 1 5 10 15 Ser Pro Val Ile Phe Leu Phe Gly Pro Ile Trp Leu Leu Ile Leu Met 20 25 30 His Gln Asn Phe Met Tyr Asn His Met Asp Leu Tyr Val Asn 35 40 45 273 32 PRT Homo sapien 273 Met Gly Arg Ala Leu Pro Leu Ser Ala Ala Pro Ser Leu Ser Leu Cys 1 5 10 15 Leu Pro Ala Gln Lys Arg Trp Leu Trp Pro Arg Gly Ser Gly Arg Asp 20 25 30 274 224 PRT Homo sapien 274 Met Ala Val Gly Asn Ile Asn Glu Leu Pro Glu Asn Ile Leu Leu Glu 1 5 10 15 Leu Phe Thr His Val Pro Ala Arg Gln Leu Leu Leu Asn Cys Arg Leu 20 25 30 Val Cys Ser Leu Trp Arg Asp Leu Ile Asp Leu Val Thr Leu Trp Lys 35 40 45 Arg Lys Cys Leu Arg Glu Gly Phe Ile Thr Glu Asp Trp Asp Gln Pro 50 55 60 Val Ala Asp Trp Lys Ile Phe Tyr Phe Leu Arg Ser Leu His Arg Asn 65 70 75 80 Leu Leu His Asn Pro Cys Ala Glu Glu Gly Phe Glu Phe Trp Ser Leu 85 90 95 Asp Val Asn Gly Gly Asp Glu Trp Lys Val Glu Asp Leu Ser Arg Asp 100 105 110 Gln Arg Lys Glu Phe Pro Asn Asp Gln Val Arg Ser Gln Ala Arg Leu 115 120 125 Arg Val Gln Val Pro Ala Val Arg Ser Ala Pro Val Val Arg Ala Arg 130 135 140 Ala Ser Gly Asp Leu Pro Ala Arg Pro Gly Asp His Pro Ala Glu Glu 145 150 155 160 Arg Cys Gln Val Glu Gly Gly Leu Pro His Ile Leu Gln Leu Pro Ala 165 170 175 Arg Arg Pro Leu His Leu Val Ser Ala Arg Arg Arg Gly His Ser Leu 180 185 190 Leu Gly Arg Leu Val Arg Pro Glu Gly His Gln Gln Gln His His His 195 200 205 Arg Ala Pro Ala Ala Leu Thr Pro Pro Glu Pro Pro Ser Ala Glu Pro 210 215 220 275 33 PRT Homo sapien 275 Met Gly Gly Gln Ala Thr Arg Tyr Tyr Ile Ile Asn Ile Leu Ser Gly 1 5 10 15 Lys Ile Ser Leu Phe Arg Ala Ile Arg Gln Val Ala Lys Asn Phe Ile 20 25 30 Leu 276 77 PRT Homo sapien 276 Met Asn Gly Lys Thr Lys Val Glu Arg Asn Ile Leu Ser Tyr Ile Ile 1 5 10 15 Leu Gln Ile Lys Thr Phe Lys Asn Gln Ile Val Phe Leu Val Leu Arg 20 25 30 Thr Asn Arg Lys Cys Leu Ile Ile Tyr Phe Ile Ser Thr Arg Gln Lys 35 40 45 Tyr Ser Tyr Ala Ala Asp Val Arg Glu Gly Gly Glu Phe Pro Gln Pro 50 55 60 Ser Met Lys Lys Asp Lys Gly Pro Tyr Pro Leu Ala Val 65 70 75 277 39 PRT Homo sapien 277 Met Tyr Val Arg Ser Ile His Leu Lys Ser Met Val Gln Ile Ala Lys 1 5 10 15 Ile Gly Pro Gly Glu Thr Cys Ser His Phe Leu Lys Thr Cys Thr Ser 20 25 30 Ala Ala Asn His Ala Thr Pro 35 278 26 PRT Homo sapien 278 Met Pro Ile Arg Leu Cys Val Cys Ala Arg Phe Leu Lys Thr Ala Asn 1 5 10 15 Tyr Ile Val Ser Ser Gln Met Ser Gly Phe 20 25 279 149 PRT Homo sapien 279 Met Leu Val Phe Ser Ala Gly Arg Leu Ala Cys Trp Arg Ala Val Cys 1 5 10 15 Trp Leu Gly Arg Cys Ala Cys Ala Ser Ser Arg Val Cys Leu Arg Leu 20 25 30 Val Leu Ser Trp Ser Arg Val Val Cys Phe Trp Trp Ser Phe Trp Leu 35 40 45 Phe Val Ser Val Val Cys Phe Val Phe Ser Cys Phe Val Ser Leu Leu 50 55 60 Cys Cys Cys Gly Val Arg Leu Tyr Phe Val Val Ser Trp Gly Val Phe 65 70 75 80 Phe Cys Asp Leu Leu Arg Cys Cys Tyr Asp Asn Val Cys Phe Ala His 85 90 95 Pro Thr Val Cys Phe Ser Ser Cys Pro Phe Phe Gly Val Leu Asn Tyr 100 105 110 Val Phe Phe Ile Leu Phe Pro His Trp Gly Val Cys Val Gly Gly Val 115 120 125 Val Pro Phe Ala Ala Val Phe Ser Gly Phe Phe Trp Ser Cys Pro Cys 130 135 140 Phe Val Ala Ala Arg 145 280 54 PRT Homo sapien 280 Met Ile Leu Lys Gly Thr Leu Thr Ile Tyr Asn Lys Ser Phe Gln Tyr 1 5 10 15 Tyr Ser Ser Ser Leu Thr Ser Glu Ser Leu Val Tyr Val Ile Leu Ser 20 25 30 Arg Lys Lys Thr Thr Tyr Lys Ser His Phe Pro Thr Lys Leu Ile Gln 35 40 45 His Pro Thr Leu Lys Ile 50 281 114 PRT Homo sapien 281 Val Ala Gly Ile Thr Gly Ile His His His Thr Gln Leu Phe Phe Cys 1 5 10 15 Ile Phe Val Arg Asp Arg Phe Leu His Val Gly Gln Ala Gly Leu Glu 20 25 30 Leu Pro Thr Ser Gly Asp Pro Pro Thr Ser Ala Ser Gln Ser Asp Asp 35 40 45 Phe Ile Phe Ile Phe Asn Cys Ile Asn Leu His Leu Asp Asn Asp Phe 50 55 60 Val Lys Gly Val Cys Cys Val Gln Asn Leu Arg Tyr Trp Leu Arg Val 65 70 75 80 Lys Tyr Ile Ile Phe Ile Ile Cys Trp Val Ala Ser Ser Tyr Ala Ala 85 90 95 Phe Phe Leu Ser Thr Phe Ile Lys Ser Ser Phe Leu Lys Leu Phe Ile 100 105 110 Ile Phe 282 171 PRT Homo sapien 282 Met Leu Phe Cys Ile Phe Thr Val Tyr Cys Phe Tyr Asn Lys Tyr Lys 1 5 10 15 Met Lys Met Phe Met Leu Thr Lys Arg Thr Lys Asn Asn Lys Gln Gln 20 25 30 Lys Thr Lys Gly Trp Gly Cys His Thr Cys Gly Pro Lys Ala Gly Phe 35 40 45 Pro Gly Gly Gly His Leu Val Leu Ser Arg Pro His Asn Ser Pro Pro 50 55 60 Lys Tyr Tyr Arg Glu Thr Thr Gly Arg Thr Thr Gln His Thr Lys Arg 65 70 75 80 His Asn Thr Gln Asn His His Thr Ala Thr Pro Ala His Arg Arg Gln 85 90 95 Arg Thr Arg Arg Glu Gln Lys Glu Lys Gly Gln Gln Lys Lys Ala Ser 100 105 110 Ser Thr Ile Thr Thr Gln Ser His Asp Lys Lys Arg Arg Thr Met Thr 115 120 125 Lys Thr Ser Ser Ser Thr Arg His Arg Gln Asp Lys Ser Lys Lys Asp 130 135 140 Arg Thr Arg Gln Lys Thr Thr Arg Asp Glu Thr Thr Lys Lys Pro His 145 150 155 160 Lys Lys Ala Ser Glu Asn Lys Asn Gln Leu Thr 165 170 283 90 PRT Homo sapien 283 Met Asn Ala Thr Val Leu Ser Val Phe Lys Ala Lys Leu Leu Trp Lys 1 5 10 15 Leu Gly Gly Gly Pro Pro Cys Gly Pro Pro Ala Ala Leu Cys Leu Pro 20 25 30 Leu Gly Ala Pro Glu Leu Met Pro Val Val Ile Ser Ala Met Leu Asp 35 40 45 Ala Arg Ser Gln Arg Ser Ala Ser Leu Ser Gln Leu Ala Cys Ala Ala 50 55 60 Leu Thr Trp Leu Pro Ala Val Leu Arg Asn Leu His Trp Trp Asp Lys 65 70 75 80 Gly Met Lys Arg Ile Asn Lys Asp Leu Lys 85 90 284 154 PRT Homo sapien 284 Lys Glu Ala Pro Ser Ser Gln Asp Ile Leu Val Phe Leu Thr Gly Gln 1 5 10 15 Glu Glu Ile Glu Ala Met Ser Lys Thr Cys Arg Asp Ile Ala Lys His 20 25 30 Leu Pro Asp Gly Cys Pro Ala Met Leu Val Leu Pro Leu Tyr Ala Ser 35 40 45 Leu Pro Tyr Ala Gln Gln Leu Arg Val Phe Gln Gly Ala Pro Lys Gly 50 55 60 Tyr Arg Lys Val Ile Ile Ser Thr Asn Ile Ala Glu Thr Ser Ile Thr 65 70 75 80 Ile Thr Gly Ile Lys Tyr Val Val Asp Thr Gly Met Val Lys Ala Lys 85 90 95 Lys Tyr Asn Pro Asp Ser Gly Leu Glu Val Leu Ala Val Gln Arg Val 100 105 110 Ser Lys Thr Gln Ala Trp Gln Arg Thr Gly Arg Ala Gly Arg Glu Asp 115 120 125 Ser Gly Ile Cys Tyr Arg Leu Tyr Thr Glu Asp Glu Phe Glu Lys Phe 130 135 140 Asp Lys Met Thr Val Pro Glu Ile Gln Arg 145 150 

We claim:
 1. An isolated nucleic acid molecule comprising (a) a nucleic acid molecule comprising a nucleic acid sequence that encodes an amino acid sequence of SEQ ID NO: 165 through 284; (b) a nucleic acid molecule comprising a nucleic acid sequence of SEQ ID NO: 1 through 164; (c) a nucleic acid molecule that selectively hybridizes to the nucleic acid molecule of (a) or (b); or (d) a nucleic acid molecule having at least 60% sequence identity to the nucleic acid molecule of (a) or (b).
 2. The nucleic acid molecule according to claim 1, wherein the nucleic acid molecule is a cDNA.
 3. The nucleic acid molecule according to claim 1, wherein the nucleic acid molecule is genomic DNA.
 4. The nucleic acid molecule according to claim 1, wherein the nucleic acid molecule is a mammalian nucleic acid molecule.
 5. The nucleic acid molecule according to claim 4, wherein the nucleic acid molecule is a hum an nucleic acid molecule.
 6. A method for determining the presence of a lung specific nucleic acid (LSNA) in a sample, comprising the steps of: (a) contacting the sample with the nucleic acid molecule according to claim 1 under conditions in which the nucleic acid molecule will selectively hybridize to a lung specific nucleic acid; and (b) detecting hybridization of the nucleic acid molecule to a LSNA in the sample, wherein the detection of the hybridization indicates the presence of a LSNA in the sample.
 7. A vector comprising the nucleic acid molecule of claim
 1. 8. A host cell comprising the vector according to claim
 7. 9. A method for producing a polypeptide encoded by the nucleic acid molecule according to claim 1, comprising the steps of (a) providing a host cell comprising the nucleic acid molecule operably linked to one or more expression control sequences, and (b) incubating the host cell under conditions in which the polypeptide is produced.
 10. A polypeptide encoded by the nucleic acid molecule according to claim
 1. 11. An isolated polypeptide selected from the group consisting of: (a) a polypeptide comprising an amino acid sequence with at least 60% sequence identity to of SEQ ID NO: 165 through 284; or (b) a polypeptide comprising an amino acid sequence encoded by a nucleic acid molecule comprising a nucleic acid sequence of SEQ ID NO: 1 through
 164. 12. An antibody or fragment thereof that specifically binds to the polypeptide according to claim
 11. 13. A method for determining the presence of a lung specific protein in a sample, comprising the steps of: (a) contacting the sample with the antibody according to claim 12 under conditions in which the antibody will selectively bind to the lung specific protein; and (b) detecting binding of the antibody to a lung specific protein in the sample, wherein the detection of binding indicates the presence of a lung specific protein in the sample.
 14. A method for diagnosing and monitoring the presence and metastases of lung cancer in a patient, comprising the steps of: (a) determining an amount of the nucleic acid molecule of claim 1 or a polypeptide of claim 6 in a sample of a patient; and (b) comparing the amount of the determined nucleic acid molecule or the polypeptide in the sample of the patient to the amount of the lung specific marker in a normal control; wherein a difference in the amount of the nucleic acid molecule or the polypeptide in the sample compared to the amount of the nucleic acid molecule or the polypeptide in the normal control is associated with the presence of lung cancer.
 15. A kit for detecting a risk of cancer or presence of cancer in a patient, said kit comprising a means for determining the presence the nucleic acid molecule of claim 1 or a polypeptide of claim 6 in a sample of a patient.
 16. A method of treating a patient with lung cancer, comprising the step of administering a composition according to claim 12 to a patient in need thereof, wherein said administration induces an immune response against the lung cancer cell expressing the nucleic acid molecule or polypeptide.
 17. A vaccine comprising the polypeptide or the nucleic acid encoding the polypeptide of claim
 11. 